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Reference 39. A simplified schema of a spinal nerve and the different types of fibers contained therein. (DC: dorsal columns; STT: spinothlamic tract). dThe excitatory amino acids (EAAs) glutamate and aspartate mediate most excitatory transmission in the CNS, including that related to nociception.33 The neuropeptide substance P activates spinal neurons and enhances their responsiveness to EAA, thus also facilitating nociception.34-38 Tissue trauma Injury signals enter the dorsal horn Motor and sympathetic reflex activity exits at the ventral horn Descending modulation Signals ascend to higher levels of the central nervous system STT DC Posterior root Spinal ganglion Posterior division Anterior root Sympathetic ganglion Aδ, C Blood vessels A Skeletal muscle δ. Aα C Aβ Receptions in skin Muscle spindle Tendon bundle la. b Viscera < DH. For example, opioid analgesics bind to opioid receptors on primary afferent and DH neurons and mimic the inhibitory effects of endogenous opioids. They also bind to opioid receptors in the brain and activate descending pathways that further inhibit DH nociceptive transmission.45 Baclofen, a GABA agonist, binds to GABAB receptors and mimics the inhibitory effects of GABA on nociceptive transmission.46 5. What Is Perception? The perception of pain is an uncomfortable awareness of some part of the body, characterized by a distinctly unpleasant sensation and negative emotion best described as threat. Both cortical and limbic system structures are involved.47 Nociceptive information from some DH projection neurons travels via the thalamus to the contralateral somatosensory cortex39 (Figure 4), where input is somatotopically mapped to preserve information about the location, intensity, and quality of the pain.43,48 The thalamus relays other nociceptive input to the limbic system.44 This input joins input from the spinoreticular and spinomesencephalic tracts to mediate affective aspects of pain.20 Immediate social and environmental context influences the perception of pain, as do past experience and culture. Consequently, a standard cause of pain (e.g., surgery) can generate enormous individual differences in pain perception. 6. What Is Modulation? a. Descending pathways Modulation of nociceptive transmission occurs at multiple (peripheral, spinal, supraspinal) levels. Yet, historically, modulation has been viewed as the attenuation of DH transmission by descending inhibitory input from the brain. Melzack and Wall’s Gate Control Theory brought this notion to the forefront in 1965.49 Models of descending pain systems now include both inhibitory and facilitory descending pathways. National Pharmaceutical Council 7 Section I: Background and Significance Figure 4. Source: Reference 22. Multiple pathways of nociceptive transmission for the spinal cord to central structures. There are four major pathways the A: spinoreticular; B: spinothalamic; C: spinomesencephalic; and D: spinohypothalamic tracts. Multiple brain regions contribute to descending inhibitory pathways.39 Nerve fibers from these pathways release inhibitory substances (e.g., endogenous opioids, serotonin, norepinephrine, GABA) at synapses with other neurons in the DH. These substances bind to receptors on primary afferent and/or DH neurons and inhibit nociceptive transmission. Such endogenous modulation may contribute to the wide variations in pain perception observed among patients with similar injuries.20,50-51 b. Clinical implications Some analgesics enhance the effects of descending inhibitory input. For example, some antidepressants interfere with the reuptake of serotonin and norepinephrine at synapses, increasing their relative interstitial concentration (availability)52-53 and the activity of endogenous pain-modulating pathways.21,50,53a Thus, some, but not all, antidepressants are used to treat some types of chronic pain. 7. What Is Peripheral Sensitization? Inflammatory mediators, intense, repeated, or prolonged noxious stimulation, or both can sensitize nociceptors.26,54-55 Sensitized nociceptors exhibit a lowered threshold for activation and an increased rate of firing.25,56-57 In other words, they generate nerve impulses more readily and more often. Peripheral (nociceptor) sensitization plays an important role in central sensitization and clinical pain states such as hyperalgesia (increased response to a painful stimulus) and allodynia (pain caused by a normally innocuous stimulus).58-59 8. What Is Central Sensitization? a. Definitions and features Central sensitization refers to a state of spinal neuron hyperexcitability.60 Tissue injury (inflammation), nerve injury (i.e., aberrant neural input), or both may cause it,27 and ongoing nociceptive input from the periphery is needed to maintain it.48 Repeated stimulation of Cnociceptors initially causes a gradual increase in the frequency of DH neuron firing known as “wind-up.”61 Activation of N-methyl D-aspartate (NMDA) receptorse plays a key role in this process.27,64-65 The clinical correlate of wind-uptemporal summation-refers to a progressive increase in pain experienced over the course of a repeated stimulus.66 Repeated or prolonged input from C-nociceptors or damaged nerves causes a longer-lasting increase in DH neuron excitability and responsiveness (i.e., central sensitizationf )67,75 which may outlast the stimulus

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