1. Pain and Analgesia PAIN IS
a submodality of somatic sensations like touch
an unpleasant sensory and emotional experience associated with actual or potential tissue damage.
individual and subjective
more than a symptom `
DIFFERENT KINDS OF PAIN:
Acute
Inflammatory
Neuropathic
Amy MacDermott, PhD Department of Physiology and Cellular Biophysics and the Center for Neurobiology and Behavior.
BB 1109,
Fig from Brain Awareness – SFN 2003

2. To understand the pharmacology of pain, you must know the anatomy and physiology of the system Peripheral nociceptors 2. Dorsal horn – major center for integration of afferent and efferent signaling 3. Ascending pathway 4. Descending pathway 
Fig from Brain Awareness – SFN 2003

3. There are multiple types of nociceptors: they can be classified by sensory modality, conduction velocity, sensitivity to growth factors, peptide expression, site of termination in the dorsal horn
Thermal
Mechanical
Chemical

4. Signal transduction in nociceptors
VR1/VRL-1
TRPV1
ASIC
CMR1
TRPM8
ENaC/DEG
TRP
Figure 2 Polymodal nociceptors use a greater diversity of signal-transduction mechanisms to detect physiological stimuli than do primary sensory neurons in other systems. a, In mammals, light or odorants are detected by a convergent signalling pathway in which G-protein-coupled receptors modulate the production of cyclic nucleotide second messengers, which then alter sensory neuron excitability by regulating the activity of a single type of cation channel. b, In contrast, nociceptors use different signal-transduction mechanisms to detect physical and chemical stimuli. Recent studies suggest that TRP-channel family members (VR1 and VRL-1) detect noxious heat, and that ENaC/DEG-channel family detect mechanical stimuli. Molecular transducers for noxious cold remain enigmatic. Noxious chemicals, such as capsaicin or acid (that is, extracellular protons) may be detected through a common transducer (VR1), illustrating aspects of redundancy in nociception. At the same time, a single type of stimulus can interact with multiple detectors, as shown by the ability of extracellular protons to activate not only VR1, but also ASICs, which are also members of the ENaC/DEG-channel family.
VR1 – vanilloid receptor 1 or TRPV1
CMR1 – cold and menthol activated receptor 1 or TRPM8
ASIC – acid sensing ion channel
Degenerin family
Modified from Julius and Basbaum, 2001

5. Nociceptor-specific Na+ channels
Dib-Hajj et al, 2002

6. Afferent fiber conduction and pain
Figure 1 Different nociceptors detect different types of pain. a, Peripheral nerves include small-diameter (A ) and medium- to large-diameter (A , ) myelinated afferent fibres, as well as small-diameter unmyelinated afferent fibres (C). b, The fact that conduction velocity is directly related to fibre diameter is highlighted in the compound action potential recording from a peripheral nerve. Most nociceptors are either A or C fibres, and their different conduction velocities (6–25 and 1.0 m s-1, respectively) account for the first (fast) and second (slow) pain responses to injury. Panel b adapted from ref. 75.
- Nociceptors include both Ad and C fibers
-- Most, but not all, small diameter fibers are nociceptors. Some are thermal and low threshold mechanoreceptors
Julius and Basbaum, 2001

7. Nociceptive inputs go to lamina I, II and V in the dorsal horn
Adapted from Fields, 1987 DH L5
Adult mammalian spinal cord

8. Two populations of nociceptors project to different sub-regions of the superficial dorsal horn
(Inflammation)
(Chronic pain)
Hunt and Mantyh, 2001

9. The spinal cord dorsal horn has a heterogeneous cell population including: -projection neurons -excitatory interneurons -inhibitory interneurons

10. Dorsal horn neurons expressing receptor for substance P, the NK1 receptor.
Lamina I
Lamina II
Lamina III
Lamina I projection neuron
Hunt and Mantyh, 2001

11. The spinal cord dorsal horn has a heterogeneous cell population including: -projection neurons -excitatory interneurons -inhibitory interneurons

12. Synaptic transmission in the dorsal horn
Nociceptors synapse with dorsal horn neurons in lamina I, II, and V
Nociceptors and local excitatory interneurons release glutamate as the fast transmitter, some also release co-transmitters such as peptides with slower excitatory action
Local inhibitory interneurons release GABA and glycine as fast transmitters, some also release co-transmitters.
Descending inputs synapse with projection neurons, interneurons, and terminals of the nociceptors

13. Glutamate receptor families
Na+,
(Ca2+?)
Ca2+
Na+,
GLU,
NMDA
GLU, KA
GLU, KA
GLU
OUT a g b IN * K+ K+
metabotropic
Glu receptors
NMDA
receptors
(NMDARs)
AMPA
receptors
Kainate
receptors

14. Synaptic transmission between nociceptors and dorsal horn neurons

15. Sensitization in the pain pathway may result in hyperalgesia (hypersensitivity to a noxious stimulus) and allodynia (pain that results from a non-noxious stimulus) Peripheral sensitization skin and viscera - Central sensitization dorsal horn higher centers

16. Thermal injury can cause hyperalgesia
Mechanical thresholds for pain were tested at sites A,B, and C before and after burns at sites A and D.
53oC stimulus at both sites for 30 sec
Mechanical thresholds for pain were tested at sites A,B, and C before and after burns at sites A and D.
53oC stimulus at both sites for 30 sec
Kandel, Schwartz Jessell Ch 24

17. Peripheral terminals of primary afferent nociceptors respond to inflammatory mediators
Figure 3 The molecular complexity of the primary afferent nociceptor is illustrated by its response to inflammatory mediators released at the site of tissue injury. Some of the main components of the 'inflammatory soup' are shown, including peptides (bradykinin), lipids (prostaglandins), neurotransmitters (serotonin (5-HT) and ATP) and neurotrophins (NGF). The acidic nature of the inflammatory soup is also indicated. Each of these factors sensitize (lower the threshold) or excite the terminals of the nociceptor by interacting with cell-surface receptors expressed by these neurons. Examples of these factors and representative molecular targets are indicated in the box. Activation of the nociceptor not only transmits afferent messages to the spinal cord dorsal horn (and from there to the brain), but also initiates the process of neurogenic inflammation. This is an efferent function of the nociceptor whereby release of neurotransmitters, notably substance P and calcitonin gene related peptide (CGRP), from the peripheral terminal induces vasodilation and plasma extravasation (leakage of proteins and fluid from postcapillary venules), as well as activation of many non-neuronal cells, including mast cells and neutrophils. These cells in turn contribute additional elements to the inflammatory soup. Figure adapted from refs 75,76.
ATP, Ach and serotonin released from damaged endothelial cells and platelets
Histamine from mast cells
Bradykinin from plasma kininogen
Julius and Basbaum, 2001

18. Central sensitization is sometimes due to neural plasticity in the spinal cord dorsal horn: - Activation of nociceptive dorsal horn neurons - Modulation producing long lasting central sensitization

19. Activation of neural plasticity in the spinal cord dorsal horn: fast EPSPs
Woolf and Salter, 2000

20. Modulation of neural plasticity in the spinal cord dorsal horn: altered connectivity and cell death
Woolf and Salter, 2000

21. Prostanoids and central sensitization

22. Ascending nociceptive pathway
Spinothalamic tract (STT)
Lamina I – mostly high threshold input, fibers cross to lateral funiculus – many projections ascend to the thalamus – carry pain and temperature info
Lamina V – some low and high threshold input, fibers cross to anterior STT – many projections as ascends to thalamus - also important in pain signaling
Spinoreticular (SRT) and
Spinomesencephalic tract (SMT)
Spinohypothalamic tract (SHT)
Textbook of pain ch 7
Wall and Melzack, Ch 7

23. Descending pathway that regulates nociceptive signaling in dorsal horn
Periaqueductal grey (PAG)
Dorsolateral pontomesencephalic tegmentum (DLMT)
Rostral ventromedial medulla (RVM)
Nucleus raphe magnus
Reticular formation
Dorsal horn
KSJ – Ch 24 – Fig 24-11
Kandel, Schwartz, Jessell Ch 24
Wall and Melzack, Ch 11

24. Descending brainstem connections for pain modulation: on and off cells
Wall and Melzack ch 11
Wall and Melzack,

25. Opioids are important regulators of nociceptive signaling and they act at many levels of the nervous system: - primary afferents - dorsal horn neurons - higher centers
(RVM)
Norepinephrine
Serotonin
Nociceptor
Projection neuron
Kandel Schwartz Jessell Ch 24

26. Opioid receptors – 3 gene families
m opioid receptor – activated by morphine, b endorphin and enkephalins
opioid receptor activated by dynorphin
d opioid receptors activated by enkephalins and b endorphin
Bonica’s Management of Pain Ch 4

27. Opioid receptor action
Bonica 4-32
Bonica’s Management of Pain Ch 4

28. Local circuit interneurons
KSJ Fig 24-13
Kandel, Schwartz, Jessell Ch 24

29. Summary:
- There are multiple types of nociceptors: they can differ by sensitivity to growth factors, peptide expression, conduction velocity, sensory modality
- All nociceptors release glutamate thus glutamate receptors are potential targets for pain management
- Sensitization occurs peripherally and centrally
- Dorsal horn neurons project to multiple higher levels in the brain and receive descending regulatory input from those same areas
- There are good targets for pain management on peripheral and central terminals of nociceptors as well as through regulation of inhibition in the dorsal horn