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, 305-3889 Fig from Brain Awareness – SFN 2003

To understand the pharmacology of pain, you must know the anatomy and physiology of the system. 1. 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

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

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

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

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

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

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

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

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

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

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

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

Synaptic transmission between nociceptors and dorsal horn neurons

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

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

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

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

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

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

Prostanoids and central sensitization

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

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

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

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

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

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

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

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