1. Innovations in ‘Omnineuromodulation’TM
May 2006
Increasingly, cannabinoids (CBs) are being used to treat a variety of diseases and symptoms. However, the mechanisms by which these agents exert their multiple therapeutic effects have only been elucidated recently. Today’s presentation describes a novel term, Omnineuromodulation™, that describes the scientific platform and mechanism of action by which CB agonists assert their therapeutic effects in the treatment of chemotherapy-induced nausea and vomiting (CINV), cachexia, and neuropathic pain (NP).

2. Introduction
Present a scientific validation for cannabinoids (CBs) asserting their therapeutic effects through ‘Omnineuromodulation’TM
CBs are CB1 agonists that activate presynaptic CB1 endocannabinoid receptors, which are omnipresent throughout the Central Nervous System (CNS)
Action on these receptors modulates neuronal signaling in important brain areas, including those that mediate nausea/vomiting, appetite, and neuropathic pain
Review evidence showing how omnineuromodulation underlies the therapeutic role of CBs in the management of Chemotherapy-Induced Nausea and Vomiting (CINV), Cachexia, and Neuropathic Pain (NP)

3. The Ubiquitous CB1
Endocannabinoids are a major class of neuromodulators, acting through CB1 receptors primarily located on CNS neurons
Levels exceed those of nearly all neurotransmitter receptors1
Endocannabinoids also activate CB2 receptors, mainly located on immune cells in the periphery2
Exogenous cannabinoids exert their effects by driving these innate systems, often mimicking and enhancing their natural functions
Activating an Innate Neuromodulatory System
The last 15 years have brought the discovery of an endogenous, or endocannabinoid, system consisting of two cannabinoid receptors—CB1 and CB2—and the two main ligands that act on these receptors, anandamide and 2-arachidonyl-glycerol (2-AG).{Croxford, 2003} CB1 receptors are primarily located on neurons of the central and peripheral nervous system, while CB2 receptors are mainly located on immune cells in the periphery.{Croxford, 2003} CB1 receptors are present in high quantities in the CNS, exceeding the levels of nearly all neurotransmitter receptors.{Martin and Wiley, 2004} Cannabinoid receptors are among the most ubiquitous neurotransmitter elements in the brain, as they exist in virtually every brain region and on many different types of neurons.{Howlett et al, 2004} They have been shown to inhibit neuronal signaling involving various neurotransmitters.{Schlicker and Kathmann, 2001} In the brain regions where CB1 receptors are especially concentrated, the normal biology and behavior associated with these brain areas are consistent with the physiological and behavioral effects produced by cannabinoids.{Martin and Wiley, 2004}
Given the omnipresent distribution and highly concentrated levels of the CB1 receptors in the nervous system, endogenous cannabinoids are considered a major class of neuromodulators.{Martin and Wiley, 2004} Exogenous cannabinoids exert their effects by driving this innate system, often mimicking and enhancing its natural functions. One example of an exogenous cannabinoid is ∆9-THC (∆9-tetrahydrocannabinol), the major psychoactive component of cannabis.{Croxford, 2003} Cesamet (nabilone) is a synthetic analog of ∆9-THC.{Cesamet (Nabilone) Prescribing Information; Ward and Holmes, 1985} Classical cannabinoids such as ∆9-THC and nabilone generally signal through both CB1 and CB2 receptors. Their therapeutic effects can be explained primarily by agonist action on these receptors {Croxford, 2003} in critical brain regions that mediate nausea/emesis, appetite, and neuropathic pain.{Martin and Wiley, 2004} This neuromodulatory effect, coupled with the omnipresent central distribution of the CB1 receptors, has led to the proposed term, “Omnineuromodulator,”TM to describe the action of exogenous cannabinoids at the innate cannabinoid receptors.
References
Cesamet (Nabilone) Prescribing Information.
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Kalant H. Medicinal use of cannabis: History and current status. Pain Res Manage Vol 6 No 2.
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci Nov;22(11):
Ward A, Holmes B. Nabilone. A preliminary review of its pharmacological properties and therapeutic use. Drugs Aug;30(2):
1..Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain.
J Support Oncol Jul-Aug;2(4):305-14; discussion Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 2003; 17:

4. The Ubiquitous CB1
The omnipresent central distribution of CB1 receptors, and the modulatory effect on neuronal signaling, has led to the term ‘Omnineuromodulator,’TM to describe CB action
Therapeutic effects are primarily due to CB1 agonist action in CNS regions that mediate nausea/vomiting, appetite, and neuropathic pain
Activating an Innate Neuromodulatory System
The last 15 years have brought the discovery of an endogenous, or endocannabinoid, system consisting of two cannabinoid receptors—CB1 and CB2—and the two main ligands that act on these receptors, anandamide and 2-arachidonyl-glycerol (2-AG).{Croxford, 2003} CB1 receptors are primarily located on neurons of the central and peripheral nervous system, while CB2 receptors are mainly located on immune cells in the periphery.{Croxford, 2003} CB1 receptors are present in high quantities in the CNS, exceeding the levels of nearly all neurotransmitter receptors.{Martin and Wiley, 2004} Cannabinoid receptors are among the most ubiquitous neurotransmitter elements in the brain, as they exist in virtually every brain region and on many different types of neurons.{Howlett et al, 2004} They have been shown to inhibit neuronal signaling involving various neurotransmitters.{Schlicker and Kathmann, 2001} In the brain regions where CB1 receptors are especially concentrated, the normal biology and behavior associated with these brain areas are consistent with the physiological and behavioral effects produced by cannabinoids.{Martin and Wiley, 2004}
Given the omnipresent distribution and highly concentrated levels of the CB1 receptors in the nervous system, endogenous cannabinoids are considered a major class of neuromodulators.{Martin and Wiley, 2004} Exogenous cannabinoids exert their effects by driving this innate system, often mimicking and enhancing its natural functions. One example of an exogenous cannabinoid is ∆9-THC (∆9-tetrahydrocannabinol), the major psychoactive component of cannabis.{Croxford, 2003} Cesamet (nabilone) is a synthetic analog of ∆9-THC.{Cesamet (Nabilone) Prescribing Information; Ward and Holmes, 1985} Classical cannabinoids such as ∆9-THC and nabilone generally signal through both CB1 and CB2 receptors. Their therapeutic effects can be explained primarily by agonist action on these receptors {Croxford, 2003} in critical brain regions that mediate nausea/emesis, appetite, and neuropathic pain.{Martin and Wiley, 2004} This neuromodulatory effect, coupled with the omnipresent central distribution of the CB1 receptors, has led to the proposed term, “Omnineuromodulator,”TM to describe the action of exogenous cannabinoids at the innate cannabinoid receptors.
References
Cesamet (Nabilone) Prescribing Information.
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Kalant H. Medicinal use of cannabis: History and current status. Pain Res Manage Vol 6 No 2.
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci Nov;22(11):
Ward A, Holmes B. Nabilone. A preliminary review of its pharmacological properties and therapeutic use. Drugs Aug;30(2):

5. Omnineuromodulation
CBs, such as CESAMET™ (nabilone), act on presynaptic CB1 receptors, similar to innate or “endo”-cannabinoids
Inhibits the release of excitatory (e.g., glutamate) and inhibitory (e.g., GABA) neurotransmitters
The primary effect on neuronal signaling appears to be inhibitory, but network effects may be complex and, hence, modulatory in nature
Endocannabinoids act in reverse from classical neurotransmitters by serving as retrograde synaptic messengers
Omnineuromodulator Action
Exogenous cannabinoid omnimodulators, such as Cesamet (nabilone), exert their effects via agonist action on the presynaptic CB1 receptors, in a manner similar to endocannabinoids.{Croxford, 2003} Evidence suggests that such activation of presynaptic CB1 receptors can lead to inhibition of the evoked release of a number of excitatory (e.g., glutamate) and inhibitory (e.g., GABA) neurotransmitters, both in the central and peripheral nervous systems.{Howlett et al, 2002; Schlicker and Kathmann, 2001} Thus, cannabinoids have been shown to inhibit GABA release in the basal ganglia and glutamate release in the cerebellum.{Freund et al, 2003} A unifying theme is the widespread occurrence of presynaptic CB1 receptors on local GABAergic interneurons.{Freund et al, 2003}
Although the primary effect of CB1 receptor agonists on neuronal signaling appears to be inhibitory, their network effects may be complex and hence modulatory in nature.{Howlett et al, 2002; Martin and Wiley, 2004} An initial inhibitory effect may trigger enhanced neurotransmitter release downstream, resulting in a net activating effect.{Howlett et al, 2002} For example, decreasing the release of the inhibitory neurotransmitter GABA can “disinhibit,” or activate, neurons with which the GABA cells are communicating. Another example of a downstream effect produced by CB1 receptor agonists is the stimulation of dopamine release in a “reward center” (the nucleus accumbens). In this case, it is likely that the cannabinoid receptor-mediated disinhibition of dopamine release stems from an inhibition of glutamate release from extrinsic glutamatergic, rather than GABAergic, fibers.{Howlett et al, 2002; Schlicker and Kathmann, 2001}
Endogenous Retrograde, or “Backward,” Signaling and Exogenous Cannabinoids
In addition to this seemingly contradictory inhibitory/excitatory effect, evidence suggests that endogenous CB1 ligands act “backwards” from classical neurotransmitters by serving as retrograde synaptic messengers.{Diana and Marty, 2004} Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5): [SEE NEXT PAGES IN SHOW]
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci Nov;22(11):

6. A Sequential Overview of Omnineuromodulation

7. Neurotransmitter (NT) released from vesicles within the presynaptic neuron activates the postsynaptic neuron
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5):
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

8. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5):
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

9. The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5):
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

10. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5):
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

11. CB agents, acting as Omnineuromodulators, circumvent this multi-step process by directly activating CB1 receptors to stimulate the endogenous CB system, enhancing its function
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5):
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

12. Anti-emetic, Anti-nausea Effects of Cannabinoids

13. Causes of nausea and vomiting/emesis: Viral illness Cancer
Chemotherapy Radiotherapy
Potential Action of Cannabinoids in Nausea and Emesis
Nausea and emesis (vomiting) occur under a variety of conditions, including viral illness, cancer, cancer chemotherapy and radiotherapy. Both are produced by excitation of one or a combination of trigger(s) located in the gastrointestinal tract, brain stem, and higher cortical and limbic centers.{Hornby, 2001} Cannabinoids are thought to exert their therapeutic effects via action on CB1 cannabinoid receptors in all three of these regions, with the best evidence being for effects in the brain.{Hornby, 2001; Dodds, 1985; Croxford, 2003}
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Dodds LJ. The control of cancer chemotherapy-induced nausea and vomiting. J Clin Hosp Pharm Jun;10(2):
Hornby PJ. Central neurocircuitry associated with emesis. Am J Med Dec 3;111 Suppl 8A:106S-112S.

14. Dorsal Vagal Complex (DVC)
The Nucleus of the Solitary Tract (NTS) in the DVC receives information about:
Blood-borne emetics via the brainstem (BS) “Chemo-receptor Trigger Zone”
Abdominal irritants via vagal afferents
NTS neurons, in turn, project to a BS central pattern generator, which coordinates vomiting behavior
Dorsal Vagal Complex (DVC)
- NTS
Brainstem Emetic Circuitry: Dorsal Vagal Complex
The central region most implicated in the effects of cannabinoids in the control of emesis is the brainstem dorsal vagal complex (DVC), and in particular the nucleus of the solitary tract (NTS) within the DVC.{Hornby, 2001; Martin and Wiley, 2004} The NTS receives information about blood-borne emetics (such as cytotoxic drugs) via chemosensitive neurons in the area postrema, referred to as the “chemo-receptor trigger zone (CTZ).” It also receives input from abdominal vagal afferents that detect local irritants (such as cytotoxic drugs, radiation, viruses) in the stomach and intestine. Neurons from the NTS, in turn, project to a brainstem central pattern generator, which coordinates the sequence of behaviors during emesis.{Hornby, 2001}
References
Hornby PJ. Central neurocircuitry associated with emesis. Am J Med Dec 3;111 Suppl 8A:106S-112S.
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion

15. Cortex Limbic System
Brainstem
Emetic
Circuitry
Higher cortical and limbic regions (governing taste, smell, sight, pain, memory and emotion) can suppress or stimulate nausea/vomiting through descending connections to the BS emetic circuitry
Higher Cortical and Limbic Regions
Cannabinoids are also believed to help control emesis via action in higher cortical and limbic regions that influence the brainstem emetic circuitry. These areas are involved in modulating complex experiences such as taste, smell, sight, and pain, as well as memory (involved in anticipatory nausea/vomiting {Grunberg, 1989}) and emotion (e.g., fear and dread). They can powerfully stimulate or suppress nausea and vomiting. Specific areas implicated include insular cortex, orbital cortex, cingulate cortex, uncus and pes hippocampus, and amygdala.{Fiol et al, 1988; Schauble et al, 2002}
Cesamet (nabilone), a synthetic analog of THC, is indicated for the management of severe nausea and vomiting associated with cancer chemotherapy.{Cesamet (Nabilone) Prescribing Information} The antiemetic action of nabilone may be triggered in the forebrain, causing inhibition of the brainstem emetic circuitry through descending connections.{Ward and Holmes, 1985} Given their sites of action and positive findings in animals, cannabinoids may also be useful as pretreatments to avoid establishment of conditioned nausea and anticipatory emesis associated with chemotherapy.{Fride et al, 2005}
References
Cesamet (Nabilone) Prescribing Information.
Fiol ME, Leppik IE, Mireles R, Maxwell R. Ictus emeticus and the insular cortex. Epilepsy Res Mar-Apr;2(2):
Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) Apr;230(4):
Grunberg SM. Advances in the management of nausea and vomiting induced by non-cisplatin containing chemotherapeutic regimens. Blood Rev Dec;3(4):
Schauble B, Britton JW, Mullan BP, Watson J, Sharbrough FW, Marsh WR. Ictal vomiting in association with left temporal lobe seizures in a left hemisphere language-dominant patient. Epilepsia Nov;43(11):
Ward A, Holmes B. Nabilone. A preliminary review of its pharmacological properties and therapeutic use. Drugs Aug;30(2):

16. Cannabinoids are thought to exert their antiemetic effects primarily via action on CB1 receptors in the NTS and higher cortical and limbic regions
Indirect, partial actions on 5-HT and DA signaling via 5-HT3 and D2 receptors are implicated
Cortex Limbic System
Brainstem Emetic Circuitry
Potential Action of Cannabinoids in Nausea and Emesis
Nausea and emesis (vomiting) occur under a variety of conditions, including viral illness, cancer, cancer chemotherapy and radiotherapy. Both are produced by excitation of one or a combination of trigger(s) located in the gastrointestinal tract, brain stem, and higher cortical and limbic centers.{Hornby, 2001} Cannabinoids are thought to exert their therapeutic effects via action on CB1 cannabinoid receptors in all three of these regions, with the best evidence being for effects in the brain.{Hornby, 2001; Dodds, 1985; Croxford, 2003}
Brainstem Emetic Circuitry: Dorsal Vagal Complex
The central region most implicated in the effects of cannabinoids in the control of emesis is the brainstem dorsal vagal complex (DVC), and in particular the nucleus of the solitary tract (NTS) within the DVC.{Hornby, 2001; Martin and Wiley, 2004} The NTS receives information about blood-borne emetics (such as cytotoxic drugs) via chemosensitive neurons in the area postrema, referred to as the “chemo-receptor trigger zone (CTZ).” It also receives input from abdominal vagal afferents that detect local irritants (such as cytotoxic drugs, radiation, viruses) in the stomach and intestine. Neurons from the NTS, in turn, project to a brainstem central pattern generator, which coordinates the sequence of behaviors during emesis.{Hornby, 2001}
Higher Cortical and Limbic Regions
Cannabinoids are also believed to help control emesis via action in higher cortical and limbic regions that influence the brainstem emetic circuitry. These areas are involved in modulating complex experiences such as taste, smell, sight, and pain, as well as memory (involved in anticipatory nausea/vomiting {Grunberg, 1989}) and emotion (e.g., fear and dread). They can powerfully stimulate or suppress nausea and vomiting. Specific areas implicated include insular cortex, orbital cortex, cingulate cortex, uncus and pes hippocampus, and amygdala.{Fiol et al, 1988; Schauble et al, 2002}
Cesamet (nabilone), a synthetic analog of THC, is indicated for the management of severe nausea and vomiting associated with cancer chemotherapy.{Cesamet (Nabilone) Prescribing Information} The antiemetic action of nabilone may be triggered in the forebrain, causing inhibition of the brainstem emetic circuitry through descending connections.{Ward and Holmes, 1985} Given their sites of action and positive findings in animals, cannabinoids may also be useful as pretreatments to avoid establishment of conditioned nausea and anticipatory emesis associated with chemotherapy.{Fride et al, 2005}
Gastrointestinal Enteric Nervous System
Finally, cannabinoids inhibit gastrointestinal transit and hence gastric emptying. They decrease fundic tone and antral motility via CB1 receptors in the enteric nervous system, and possibly via action in the DVC. These actions could possibly contribute to the antiemetic effects of cannabinoids. {Hornby, 2001; Croxford, 2003} However, the exact mechanism by which this may occur is unclear.
Modulation of Neuronal Signaling
A variety of neurotransmitter systems are involved in the complex process of nausea/vomiting, and cannabinoids are thought to assert a primarily inhibitory affect on neurotransmitter release.{Schlicker and Kathmann, 2001; Howlett et al, 2002; Freund et al, 2003} Serotonin (5-HT) and dopamine (DA) are involved in transmission of peripheral stimuli to the brainstem,{Hornby, 2001; Dodds, 1985; Grunberg, 1989} Indirect, partial actions on 5-HT and DA neurotransmission via 5-HT3 and D2 receptors have been implicated in cannabinoid antiemetic effects.{Nahas et al, 2002} The antiemetic action of nabilone is not believed to be mediated primarily by a DA path, however, although there may be some activity at the CTZ.{Ward and Holmes, 1985}
References
Cesamet (Nabilone) Prescribing Information.
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Dodds LJ. The control of cancer chemotherapy-induced nausea and vomiting. J Clin Hosp Pharm Jun;10(2):
Fiol ME, Leppik IE, Mireles R, Maxwell R. Ictus emeticus and the insular cortex. Epilepsy Res Mar-Apr;2(2):
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) Apr;230(4):
Grunberg SM. Advances in the management of nausea and vomiting induced by non-cisplatin containing chemotherapeutic regimens. Blood Rev Dec;3(4):
Hornby PJ. Central neurocircuitry associated with emesis. Am J Med Dec 3;111 Suppl 8A:106S-112S.
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion
Nahas G, Harvey DJ, Sutin K, Turndorf H, Cancro R. A molecular basis of the therapeutic and psychoactive properties of cannabis (delta9-tetrahydrocannabinol). Prog Neuropsychopharmacol Biol Psychiatry May;26(4):
Schauble B, Britton JW, Mullan BP, Watson J, Sharbrough FW, Marsh WR. Ictal vomiting in association with left temporal lobe seizures in a left hemisphere language-dominant patient. Epilepsia Nov;43(11):
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci Nov;22(11):
Ward A, Holmes B. Nabilone. A preliminary review of its pharmacological properties and therapeutic use. Drugs Aug;30(2):
Dorsal Vagal Complex
- NTS

17. Potential Action of Cannabinoids in Cachexia

18. Hypothalamus Feeding Circuitry Ventral Tegmental Areas (VTA)
Cannabinoids can stimulate appetite and increase food intake by:
Acting on CB1 receptors in the Hypothalamus, which plays a key role in homeostatic regulation of energy balance
Acting on CB1 receptors in the Nucleus Accumbens and activating an important Reward Path that connects the VTA and Nucleus Accumbens, which enhances attractiveness/ enjoyment of food, thus increasing incentive to eat
Nucleus Accumbens Reward Path
Hypothalamus Feeding Circuitry
Potential Action of Cannabinoids in Cachexia
Cachexia or wasting is a common feature of the later stages of diseases such as metastatic cancer and AIDS. The significant loss of lean body weight that occurs is due to a reduction in appetite, as well as abnormalities in lipid and glucose metabolism. Unlike starved individuals, patients with cachexia do not respond to the negative energy imbalance with a compensatory increase in motivation to eat.{Fride et al, 2005} Cannabinoids are known to lead to robust increases in food intake and can promote body weight gain.{Vickers and Kennett, 2005} Their appetite-stimulating effects are thought to be mediated through action on CB1 cannabinoid receptors in brain centers that regulate homeostatic and rewarding aspects of food intake. Additionally, cannabinoids may also act on peripheral CB1 receptors which are involved in the regulation of satiety signals and metabolism. Currently, the best evidence for these potentially therapeutic effects pertains to the hypothalamic feeding circuitry.{Harrold and Williams, 2003; Fride et al, 2005; Martin and Wiley, 2004}
Hypothalamic Feeding Circuitry: The Endocannabinoid System and Leptin
Cannabinoid agonist drugs can increase food intake by acting on CB1 receptors within the hypothalamus, thereby activating the endogenous cannabinoid system which regulates feeding.{Harrold and Williams, 2003} The hypothalamus plays a key role in the homeostatic regulation of energy balance, or the instigation of food seeking and eating initiation (referred to as food “wanting”).{Harrold and Williams, 2003; Fride et al, 2005} Endogenous cannabinoids modulate these complex integrative processes to stimulate appetite, and thus hypothalamic cannabinoid activity varies according to changes in nutritional status and the expression of feeding behaviors.{Cota et al, 2003; Fride et al, 2005} These changes in turn are under partial negative control of the hormone leptin.{Cota et al, 2003} Leptin is an important circulating satiety factor that originates in adipocytes (fat cells) and exerts an anorectic effect in the hypothalamus.{Fride et al, 2005} Thus, as leptin levels decrease, endocannabinoid levels increase resulting in increased appetite, and vice versa.{Cota et al, 2003; Vettor et al, 2002} By driving the endocannabinoid system in the hypothalamus to stimulate appetite, exogenous cannabinoids in effect circumvent control by leptin.
Reward Pathway: Nucleus Accumbens, Dopamine and Opioids
Cannabinoid agonist drugs are also thought to stimulate appetite by acting on CB1 receptors in the nucleus accumbens “reward center,” thus enhancing the attractiveness and enjoyment of food.{Cota et al, 2003; Fride et al, 2005} Evidence suggest this is due to cannabinoid interactions with both the dopamine and opioid systems.{Cota et al, 2003; Fride et al, 2005}
An important “reward path” in the brain is that which connects the ventral tegmental area (VTA) with the nucleus accumbens, referred to as the mesolimbic dopamine system. This circuit is implicated in the orosensory pleasure produced by natural rewards, including food (food “liking”).{Cota et al, 2003; Fride et al, 2005} Activation of this path by cannabinoids may increase the incentive or motivation to eat, especially stimulating the appetite for sweet, palatable foods.{Cota et al, 2003; Harrold and Williams, 2003} Specifically, neurons in the VTA send dopaminergic (DA) signals to the nucleus accumbens, and cannabinoids can indirectly enhance this DA neurotransmission, {Howlett et al, 2002; Schlicker and Kathmann, 2001} resulting in a craving for tasty food.{Cota et al, 2003}
References
Cota D, Marsicano G, Lutz B, Vicennati V, Stalla GK, Pasquali R, Pagotto U. Endogenous cannabinoid system as a modulator of food intake. Int J Obes Relat Metab Disord Mar;27(3):
Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) Apr;230(4):
Harrold JA, Williams G. The cannabinoid system: a role in both the homeostatic and hedonic control of eating? Br J Nutr Oct;90(4):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci Nov;22(11):
Vettor R, Fabris R, Pagano C, Federspil G. Neuroendocrine regulation of eating behavior. J Endocrinol Invest Nov;25(10):
Vickers SP, Kennett GA. Cannabinoids and the regulation of ingestive behaviour. Curr Drug Targets Mar;6(2):
Ventral Tegmental Areas (VTA)
[Updated]

19. Hypothalamus Feeding Circuitry
Nucleus Accumbens Reward Path
Ventral Tegmental Area (VTA)
Leptin Hormone
CBs drive the innate cannabinoid system in the hypothalamus to stimulate feeding, and circumvent the partial negative control of the circulating satiety factor leptin hormone1-2
CBs also increase motivation to eat through interaction with the dopamine and opioid systems in the Reward Path1,3
Potential Action of Cannabinoids in Cachexia
Hypothalamic Feeding Circuitry: The Endocannabinoid System and Leptin
Cannabinoid agonist drugs can increase food intake by acting on CB1 receptors within the hypothalamus, thereby activating the endogenous cannabinoid system which regulates feeding.{Harrold and Williams, 2003} The hypothalamus plays a key role in the homeostatic regulation of energy balance, or the instigation of food seeking and eating initiation (referred to as food “wanting”).{Harrold and Williams, 2003; Fride et al, 2005} Endogenous cannabinoids modulate these complex integrative processes to stimulate appetite, and thus hypothalamic cannabinoid activity varies according to changes in nutritional status and the expression of feeding behaviors.{Cota et al, 2003; Fride et al, 2005} These changes in turn are under partial negative control of the hormone leptin.{Cota et al, 2003} Leptin is an important circulating satiety factor that originates in adipocytes (fat cells) and exerts an anorectic effect in the hypothalamus.{Fride et al, 2005} Thus, as leptin levels decrease, endocannabinoid levels increase resulting in increased appetite, and vice versa.{Cota et al, 2003; Vettor et al, 2002} By driving the endocannabinoid system in the hypothalamus to stimulate appetite, exogenous cannabinoids in effect circumvent control by leptin.
Reward Pathway: Nucleus Accumbens, Dopamine and Opioids
Cannabinoid agonist drugs are also thought to stimulate appetite by acting on CB1 receptors in the nucleus accumbens “reward center,” thus enhancing the attractiveness and enjoyment of food.{Cota et al, 2003; Fride et al, 2005} Evidence suggest this is due to cannabinoid interactions with both the dopamine and opioid systems.{Cota et al, 2003; Fride et al, 2005}
An important “reward path” in the brain is that which connects the ventral tegmental area (VTA) with the nucleus accumbens, referred to as the mesolimbic dopamine system. This circuit is implicated in the orosensory pleasure produced by natural rewards, including food (food “liking”).{Cota et al, 2003; Fride et al, 2005} Activation of this path by cannabinoids may increase the incentive or motivation to eat, especially stimulating the appetite for sweet, palatable foods.{Cota et al, 2003; Harrold and Williams, 2003} Specifically, neurons in the VTA send dopaminergic (DA) signals to the nucleus accumbens, and cannabinoids can indirectly enhance this DA neurotransmission, {Howlett et al, 2002; Schlicker and Kathmann, 2001} resulting in a craving for tasty food.{Cota et al, 2003}
Endogenous opioids are also linked to central reward processes, and there is evidence for an important functional crosstalk between the endogenous cannabinoid and opioid systems in relation to appetite. There is a synergistic interaction, which appears to arise due to regulation of converging pathways.{Cota et al, 2003} Although the mechanism of interaction between these two systems has not been clarified, the evidence indicates that cannabinoids affect the motivation to eat, in part through action on the opioid system.{Cota et al, 2003}
References
Cota D, Marsicano G, Lutz B, Vicennati V, Stalla GK, Pasquali R, Pagotto U. Endogenous cannabinoid system as a modulator of food intake. Int J Obes Relat Metab Disord Mar;27(3):
Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) Apr;230(4):
Harrold JA, Williams G. The cannabinoid system: a role in both the homeostatic and hedonic control of eating? Br J Nutr Oct;90(4):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci Nov;22(11):
Vettor R, Fabris R, Pagano C, Federspil G. Neuroendocrine regulation of eating behavior. J Endocrinol Invest Nov;25(10):
1. Cota et al, 2003
2. Harrold and Williams, 2003
3. Fride et al, 2005

20. CBs may also promote feeding by acting on CB1 receptors in the Enteric Nervous System to modulate gut-derived satiety signals, such as the peptide cholecystokinin (CCK)
Enteric Nervous System
There is increasing evidence that cannabinoid agonist drugs may also promote feeding via action on CB1 receptors located on nerve terminals innervating the gastrointestinal tract (the peripheral enteric nervous system).{Vickers and Kennett, 2005} It is believed that cannabinoids modulate gut-derived satiety signals, with one candidate being the peptide cholecystokinin (CCK).{Harrold and Williams, 2003; Fride et al, 2005} There is also some evidence that cannabinoid agonists may act on CB1 receptors on adipocytes to enhance lipogenesis.{Fride et al, 2005; Vickers and Kennett, 2005} Such an action could be beneficial in inducing weight gain in cachexia, which involves metabolic abnormalities such as reduced lipogenesis.{Fride et al, 2005}
References
Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) Apr;230(4):
Harrold JA, Williams G. The cannabinoid system: a role in both the homeostatic and hedonic control of eating? Br J Nutr Oct;90(4):
Vickers SP, Kennett GA. Cannabinoids and the regulation of ingestive behaviour. Curr Drug Targets Mar;6(2):

21. CBs may act on CB1 receptors on Adipocytes to enhance lipogenesis and induce weight gain
Enteric Nervous System
There is increasing evidence that cannabinoid agonist drugs may also promote feeding via action on CB1 receptors located on nerve terminals innervating the gastrointestinal tract (the peripheral enteric nervous system).{Vickers and Kennett, 2005} It is believed that cannabinoids modulate gut-derived satiety signals, with one candidate being the peptide cholecystokinin (CCK).{Harrold and Williams, 2003; Fride et al, 2005} There is also some evidence that cannabinoid agonists may act on CB1 receptors on adipocytes to enhance lipogenesis.{Fride et al, 2005; Vickers and Kennett, 2005} Such an action could be beneficial in inducing weight gain in cachexia, which involves metabolic abnormalities such as reduced lipogenesis.{Fride et al, 2005}
References
Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) Apr;230(4):
Harrold JA, Williams G. The cannabinoid system: a role in both the homeostatic and hedonic control of eating? Br J Nutr Oct;90(4):
Vickers SP, Kennett GA. Cannabinoids and the regulation of ingestive behaviour. Curr Drug Targets Mar;6(2):
Adipocytes

22. Potential Action of Cannabinoids in Neuropathic Pain (NP)

23. What is NP?
NP is caused by primary lesion or dysfunction of the nervous system
Generally chronic
Highly unresponsive to traditional analgesics
Hallmark symptoms include hyperalgesia and allodynia
Peripheral and central pathophysiological mechanisms may be involved, including an overstimulation and hyperexcitability of nerve paths
Given the multiple pathologic mechanisms underlying NP and multiple targeting of CBs, CB agents represent a promising potential therapy
Potential Action of Cannabinoids in Neuropathic Pain
Neuropathic pain is caused by primary lesion or dysfunction of the nervous system, {Mbvundula et al, 2004} multiple pathological mechanisms underlie its occurrence, even within a single disease or individual patient.{Baron, 2000} Neuropathic pain is generally chronic in nature, and highly unresponsive to traditional analgesics.{Baron, 2000; Mbvundula et al, 2004} Hallmark symptoms of neuropathic pain include hyperalgesia (the lowering of pain threshold and an increased response to noxious stimuli) and allodynia (the evocation of pain by non-noxious stimuli).{Jensen et al, 2001} Both peripheral and central pathophysiological mechanisms may be involved, including an overstimulation and hyperexcitability of nerve paths.{Baron, 2000} Acute pain resulting from stimulation of sensory neurons (nociceptors) can progress to chronic pain, although neuropathic pain does not always involve nociceptors.{Zimmermann, 2001} Chronic pain may also be maintained by persistent inflammatory reactions, which can lead to potentiation of nociceptor activation.{Baron, 2000; Mbvundula et al, 2004}
A profile of multiple targeting makes cannabinoid drugs attractive potential therapy for neuropathic pain. Natural and synthetic cannabinoids can reduce nociception, reverse the development of allodynia and hyperalgesia, and reduce inflammation.{Mbvundula et al, 2004} These effects are mediated by CB1 receptors in the nervous system and by CB2 receptors in the immune system.{Cravatt and Lichtman, 2004}
References
Baron R. Peripheral neuropathic pain: from mechanisms to symptoms. Clin J Pain Jun;16(2 Suppl):S12-20.
Cravatt BF, Lichtman AH. The endogenous cannabinoid system and its role in nociceptive behavior. J Neurobiol Oct;61(1):
Jensen TS, Gottrup H, Sindrup SH, Bach FW. The clinical picture of neuropathic pain. Eur J Pharmacol Oct 19;429(1-3):1-11.
Mbvundula EC, Rainsford KD, Bunning RA. Cannabinoids in pain and inflammation. Inflammopharmacology. 2004;12(2):
Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol Oct 19;429(1-3):23-37.

24. PeriAqueductal Gray matter (PAG) Rostral Ventromedial Medulla (RVM)
CBs act in the PAG, the RVM, and the Lateral Tegmental NA Cell System to dampen pain signals in the spinal cord
PeriAqueductal Gray matter (PAG)
Specifically, CBs are thought to decrease release of the inhibitory neurotransmitter GABA, which in turn, activates (disinhibits) these natural descending analgesic pathways
Pain Control Descending Pathway: PAG, RVM, Noradrenergic Cell System
Cannabinoid agonist drugs can dampen pain signals by acting on descending brain pathways that inhibit nociceptive neurons in the dorsal horn of the spinal cord.{Maldonado and Valverde, 2003} These innate pathways allow for a central control over pain transmission, and cannabinoids enhance their function at various sites via multiple mechanisms.{Maldonado and Valverde, 2003; Mbvundula et al, 2004; Freund et al, 2003} The periaqueductal gray matter (PAG), the rostral ventromedial medulla (RVM), and the lateral tegmental noradrenergic cell system have all been implicated in such cannabinoid analgesic effects.{Maldonado and Valverde, 2003; Walker and Huang, 2002}
In the PAG and RVM, cannabinoid agonists reduce the release of the inhibitory neurotransmitter GABA from local interneurons.{Maldonado and Valverde, 2003} This action in the RVM is thought to indirectly stimulate or disinhibit serotonin (5-HT) cells in the raphe magnus that project to the spinal cord.{Vaughan et al, 1999} One can speculate that a similar disinhibitory action contributes to the activation of the descending noradrenergic (NA) system in the pons. Therefore cannabinoids are hypothesized to alleviate pain, in part by boosting the body’s natural descending analgesic paths normally inhibited by the GABAergic system.{Maldonado and Valverde, 2003}
References
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Maldonado R, Valverde O. Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses. Eur Neuropsychopharmacol Dec;13(6):
Mbvundula EC, Rainsford KD, Bunning RA. Cannabinoids in pain and inflammation. Inflammopharmacology. 2004;12(2):
Vaughan CW, McGregor IS, Christie MJ. Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br J Pharmacol Jun;127(4):
Walker JM, Huang SM. Cannabinoid analgesia. Pharmacol Ther Aug;95(2):
Lateral Tegmental
Noradrenergic (NA)
Cell System
Rostral Ventromedial Medulla (RVM)

25. Ventral Posterolateral Nucleus (VPL)
CBs weaken ascending pain messages by suppressing noxious stimulus-evoked activity in the VPL of the Thalamus, and are thereby thought to decrease pain sensitivity
Ventral Posterolateral Nucleus (VPL)
Ascending Pain Path: VPL of Thalamus
Cannabinoids weaken ascending pain messages within an important nociceptive path, the spinothalamic tract.{Mbvundula et al, 2004} Specifically, cannabinoid agonists have been shown to suppress noxious stimulus-evoked activity in the ventral posterolateral nucleus (VPL) of the thalamus, and are thereby thought to decrease pain sensitivity.{Martin et al, 1996; Maldonado and Valverde, 2003; Mbvundula et al, 2004}
References
Maldonado R, Valverde O. Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses. Eur Neuropsychopharmacol Dec;13(6):
Martin WJ, Hohmann AG, Walker JM. Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: correlation between electrophysiological and antinociceptive effects. J Neurosci Oct 15;16(20):
Mbvundula EC, Rainsford KD, Bunning RA. Cannabinoids in pain and inflammation. Inflammopharmacology. 2004;12(2):

26. Amygdala-mediated analgesic effects of CBs may diminish the unpleasant emotional experience that is a component of pain
Amygdala
(Emotion)
Amygdala and Emotion
The amygdala is a primary site for cannabinoid agonist analgesia.{Piomelli, 2003; Maldonado and Valverde, 2003} This limbic center plays an important role in modulating emotions, and endogenous cannabinoids in this region are thought to have anxiolytic properties.{Piomelli, 2003} One can speculate that amygdala-mediated analgesic effects have to do with diminishing the unpleasant emotional experience that is a component of pain (as defined by The International Association for the Study of Pain).
References
Maldonado R, Valverde O. Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses. Eur Neuropsychopharmacol Dec;13(6):
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

27. Dorsal Root Ganglion (DRG)
CBs produce antinociception in the SC by modulating evoked responses of primary sensory fibers (nociceptors) in the Dorsal Horn, via a presynaptic action on DRG neurons
CBs act on CB1 receptors to inhibit glutamate release from nociceptors in the SC, reducing excitatory signaling (via NMDA) that mediates the central sensitization of pain
Dorsal Root Ganglion (DRG)
Spinal Cord Dorsal Horn
The spinal cord is an important site for cannabinoid antinociception. Cannabinoid agonists act on CB1 receptors to inhibit the release of neurotransmitters responsible for pain transmission. Important in this regard, is that cannabinoids modulate the evoked responses of C- and A- primary sensory fibers in the dorsal horn, via a presynaptic action on dorsal root ganglion (DRG) neurons.{Maldonado and Valverde, 2003}
Several mechanisms are thought to mediate these analgesic effects. A key action of cannabinoids is on the excitatory glutamate/NMDA system. NMDA glutamate receptors play a critical role in central sensitization, or the process that leads to a state of heightened sensitivity and hyperexcitability of dorsal horn neurons involved in pain transmission.{Zimmermann, 2001; Russo, 2004} Cannabinoid agonists, such as THC, inhibit glutamate release from nociceptors, and thereby reduce excitatory signaling mediating sensitization.{Russo, 2004; Freund et al, 2003}
Additionally, cannabinoids inhibit the release of modulatory neuropeptides that sensitize nociceptors. Substance P and calcitonin-gene-related peptide (CGRP) release from DRG neurons have been shown to be inhibited, and this is in part thought to underlie cannabinoid anti-nociceptive effects.{Freund et al, 2003; Mbvundula et al, 2004}
References
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Maldonado R, Valverde O. Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses. Eur Neuropsychopharmacol Dec;13(6):
Mbvundula EC, Rainsford KD, Bunning RA. Cannabinoids in pain and inflammation. Inflammopharmacology. 2004;12(2):
Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett Feb-Apr;25(1-2):31-9.
Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol Oct 19;429(1-3):23-37.
Spinal Cord (SC)

28. CBs may act on CB1 receptors located on the peripheral terminals of Primary Sensory Neurons (Nociceptors) to inhibit pain transmission
CBs may also act on CB2 receptors on surrounding immune cells to decrease inflammation and nociceptor excitation, reducing pain sensitivity
Nociceptor Peripheral Terminals
Peripheral Sensory Nerves and Immune System (not illustrated)
Cannabinoid agonists may also act on CB1 receptors located on the peripheral terminals of primary sensory neurons (nociceptors) to inhibit pain transmission.{Maldonado and Valverde, 2003} In addition, cannabinoid action on CB2 receptors located on non-neuronal cells (primarily immune cells) in surrounding tissues is thought to inhibit the release of inflammatory mediators that excite nociceptors.{Maldonado and Valverde, 2003; Mbvundula et al, 2004} Specifically, cannabinoids have been proposed to inhibit release of prostaglandins and the production of pro-inflammatory cytokines by immune cells, and to inhibit the release of histamine from neighboring mast cells.{Mbvundula et al, 2004; Cravatt and Lichtman, 2004} Indeed, it has been suggested that there is a synergistic effect of cannabinoids on CB1 and CB2 receptors in the periphery on the reduction of pain sensitivity.{Maldonado and Valverde, 2003}
References
Cravatt BF, Lichtman AH. The endogenous cannabinoid system and its role in nociceptive behavior. J Neurobiol Oct;61(1):
Maldonado R, Valverde O. Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses. Eur Neuropsychopharmacol Dec;13(6):
Mbvundula EC, Rainsford KD, Bunning RA. Cannabinoids in pain and inflammation. Inflammopharmacology. 2004;12(2):

29. Cannabinoid and Opioid Synergism
Combination therapy with CB agents and opioids may be an effective approach for NP
CB and opioid systems appear to work synergistically to reduce pain, by producing analgesic effects in converging brain pathways via different mechanisms
E.g., both activate the descending analgesic pathway in the RVM and PAG by blocking inhibitory GABA inputs
Opioid analgesics are considered less effective for NP than inflammatory pain, possibly due to depletion of opioid receptors in the spinal cord following peripheral nerve injury
In contrast, there is an upregulation of CB1 receptors in the thalamus which may increase analgesic efficacy of CBs in chronic pain conditions
Cannabinoid and Opioid Synergism
There is increasing evidence that the cannabinoid and opioid systems can work synergistically to reduce pain. This is explained by their action on converging pathways via different mechanisms.{Cichewicz, 2004; Maldonado and Valverde, 2003; Vaughan et al, 1999}
The cannabinoid and opioid systems both have analgesic effects by acting on similar structures in the central and peripheral nervous systems. For example, both activate the pain control descending pathway in the RVM and PAG by blocking inhibitory GABA inputs.{Maldonado and Valverde, 2003} However, while cannabinoids act presynaptically, opioids act both pre- and postsynaptically in the RVM.{Vaughan et al, 1999} This means that while a cannabinoid or opioid working alone on GABAergic neurons might not be strong enough to produce inhibition, they may produce inhibition of pain signals when working together.
There are bidirectional interactions between cannabinoids and opioids, sometimes referred to as “cross-talk.” In this regard, cannabinoid agonist administration increases the release of several endogenous opioid peptides in different CNS structures, including dynorphin levels in the spinal cord.{Maldonado and Valverde, 2003} However, the pain reducing effects of cannabinoid and opioid drugs may be mediated by different types of opioid receptors.{Cichewicz, 2004; Maldonado and Valverde, 2003} This distinct receptor mechanism is another reason the two drug classes may work synergistically.
It is generally accepted that opioid analgesics are less effective when used to treat neuropathic pain than inflammatory pain.{Rice et al, 2002} One reason for this may be that following peripheral nerve injury there is a depletion of opioid receptors, but not CB1 receptors, in the dorsal horn of the spinal cord. On the other hand, there is an upregulation of CB1 receptors in the thalamus that is hypothesized to contribute to increased analgesic efficacy of cannabinoids in chronic pain conditions.{Rice et al, 2002; Siegling et al, 2001} Combination therapy which targets multiple mechanisms of action may therefore be the best option.{Mbvundula et al, 2004}
References
Cichewicz DL. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci Jan 30;74(11):
Maldonado R, Valverde O. Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses. Eur Neuropsychopharmacol Dec;13(6):
Mbvundula EC, Rainsford KD, Bunning RA. Cannabinoids in pain and inflammation. Inflammopharmacology. 2004;12(2):
Rice AS, Farquhar-Smith WP, Nagy I. Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot Essent Fatty Acids Feb-Mar;66(2-3):
Siegling A, Hofmann HA, Denzer D, Mauler F, De Vry J. Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain. Eur J Pharmacol Mar 9;415(1):R5-7.
Vaughan CW, McGregor IS, Christie MJ. Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br J Pharmacol Jun;127(4):

30. Summary
CB agonists act as Omnineuromodulators —a term that describes their role in activating CB1 endocannabinoid receptors, which are omnipresent throughout the CNS and modulate neuronal signaling
Evidence shows that Omnineuromodulation underlies the therapeutic role of CB agents in the treatment of CINV, Cachexia, and NP
Given potential synergy between CB and opioid systems, combination therapy for NP may be a more effective approach

31. Approved for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments

32. CESAMET™ delivers:1
Convenient BID dosing: The usual adult dosage is 1 or 2 mg BID
Predictable pharmacokinetics: Peak plasma concentrations occur within 2 hours following oral administration
Long acting: 8 to 12 hour duration of action
Not detected by the EMIT test2
In anti-emetic phase III studies, involving 316 cancer patients receiving a variety of chemotherapeutics (including cisplatin), CESAMET™ was shown to be superior in efficacy to placebo, as well as to prochlorperazine, in:1
Reduction of vomiting episodes
Reduction of nausea severity
Improvement in appetite
Investigators’ global impression of efficacy3
References
CESAMETTM (nabilone) Package Insert.
Fraser AD and Meatherall R. Lack of intereference by nabilone in the EMIT d.a.u. cannbiniod assay, Abbot TDx Cannabiniod Assay and a sensitive TLC assay for 9-THC- carboxylic acid. J Analytic Tox 1989:
3. Data on File: Protocol #20 and #28. Valeant Pharmaceuticals.