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PAIN: BASIC MECHANISMS INTRODUCTION und affective and cognitive features: vays in the Pain is a complex perception that has profot Pain is not a stimulus. There are no pain fibers and no pain pathw: brain. Whether or not a particular stimulus will be perceived as painful depends on the nature of the stimulus, the situation in which it is experienced, memories, emotions, and so on. DEFINITION OF PAIN ence associated with actual or “An unpleasant sensory and emotional experi potential tissue damage” (Internationai Association tor Study of Pain - TASP). TYPES OF PERSISTENT/CHRONIC PAIN NOCICEPTIVE/INFLAMMATORY PAIN Examples include muscle and joint pain (such as-back pain), components of cancer pain, and tension headache. This type of pain is produced by tissue injury and is associated with inflammation; it involves activation of A delta and C fibers. It is responsive to NSAIDS and opiates (morphine). NEUROPATHIC PAIN include postherpetic neuralgia, complex regional pain syndrome limb pain. This type of pain arises from injury to the quatity. Generally it is peripheral or central nervous system; it often is burning in less responsive to opioids, but it may respond to local anesthetics, anticonvulsants, or tricyclic antidepressants. PRIMARY AFFERENT NOCICEPTORS Examples (CRPS), and phantom MECHANISMS OF SENSITIZATION Although there are no “pain” fibers in the perip! system, there are anatomically and physiologically specialized peripheral afferent fibers that respond to noxious stimuli. These thinly myelinated A delta and unmyelinated C afferents terminate as free, unencapsulated peripheral nerve endings. Physiological specificity at the level of the primary affere following: (1) Nerve compression first blocks large mechanosensation, sensations mediated by small-diam' perception of noxious stimuli are the last to disappear. (2) Loci block small-diameter fibers earliest and abolish pain first. stimulation of single primary afferents in the conscious human su pain only when thresholds for A delta or C fibers are reached. 5) hery or in the central nervous nt is indicated from the fibers and nonpainful eter fibers and the ‘al anesthetics (3) Electrical bject evokes painful” stimuli, they are \ ne . sence of AB, affe' it tereentions re omenon indiena yh the tanger APT uaiity of Boos burning. noter fibers are blocked, | range dior the level of the dorsa, | thou! necessary for the nor fi u eived : fibers, all noxious stimu! in wen ee that specificity, ¢ ats “son i ergence of the a comemiiicatspneromerers LG ost common problem AND HYPERAI . Perel o ALLODYNIA + most patients complal ot Fovernent, fight touch) become Allodynia- STE are normall not rae re BY SES errburned sin clude pain is that stimuli painful. Examples of allodynia Im ent of an arthritic joint. ; or move core po 7 ee 1 Hyperalgesi Hyperalgesia 'S happens (e.g., siapping sunburned skin oF what | ap oh presented to a subject in whose arm Primary Sensitization. When there is tissue Oe the non-noxioUs range, the Ac and C nociceptive afferent is lowered H ° ie brane lipids, via the Mechanisms involve synthesis of arachidonic acid rol He ars aeeealuponiby the steroid-sensitive enzyme phospholipase Se en s Rei eciy ion the rost 7 oa Cs Ce : their threshold to natural ‘can now activate aC peripheral terminais of Ax and C fibers Ser ie i. it ical threshold is unchanged) light to J stimuli. (Their electrical tt Leet cease’ Wey fiber and produce pain. Aspirin and other NSAIDS are ¢' inhibit cyclooxygenase. Celecoxib and rofecoxib are drugs that selectively block the COX-2 enzyme. To the extent that the COX-1 enzyme (which is. blocked by aspirin, ibuprofen, etc.) underlies side effects of NSAIDs, the COX-2 inhibitors may have particular utility. duced by noxious stimulus when nexious stimuli are ocked by compression). the threshold for firing of SUBSTANCE-P An il-amino acid peptide neurotransmitter synthesized by primary afferent nociceptors, substance P is released in the dorsal horn and activates second- order pain” transmission neurons in the dorsal horn. It is released from the peer terminals of C fibers and contributes to local, neurogenic inflammato! rechanisms, including vasodilatation, warmth (calor), redness (rubor), a " swelling (tumor). CAPSAICIN SPINAL CORD LAMINAR ORGANIZATION In 1954 Rexed demonstrated that the inal n 1954 grey matter of the spinal I divided into cytoarchitecturally distinct 10 laminae or layers. Physiological studies have since demonstrated an analogous, functional laminar organization. An electrode penetrating the grey matter of the dorsal horn records cells in the following sequence. Following are important. Lamina I (marginal layer) cells respond primarily, and in some cases exclusively, to noxious stimuli. _Some also respond io innoxious, i.e., non-injurious stimulation. Many lamina I cells contribute axons to the spinothalamic tract. wollte II (substantia gelatinosa) contains small interneurons, many of which respond to noxious inputs. Lamina II neurons modulate ceils of laminae I and V. estas I an II receive direct primiary afferent input only from small-diameter ella III and IV cells respond to innocuous stimuli, hair brush, and tactile skin stimulation, and do not increase their response when the receptive field is pinched, i.e., with noxious stimulation. Lamina V cells respond to noxious and non-noxious stimuli and are wide- dynamic-range (WDR) cells. They also respond to noxious viscera! stimuli and receive excitatory input from large- and small-diameter efferent fibers. cord could be Lamina VI cells respond to joint movement as well as to cutaneous stimulation. PHYSIOLOGY OF THE WiDE-DYNAMIC-RANGE CELL In addition to convergence of different modalities of input, WOR neurons in lamina V receive inputs from a relatively large area in a phenomenon known as spatial convergence. In fact, single cells in lamina V of the dorsal horn of the ve a complex receptive field consisting of at least two distinct spinal cord ha d noxious stimull” regions. In the center of the receptive field both innocuous an are excitatory. In the surrounding regions, non-noxious stimuli (carried by large fibers) are inhibitory. This factor presumably accounts for the pain-relieving effects of shaking one’s hand or receiving vibratory stimuli or transcutaneous electrical nerve stimulation (TENS). By contrast, removal of the inhibitory components of the receptive field (e.g., after nerve injury) might increase the a noxious stimulus. Thus, lesions that cause selective response of a WDR cell to damage to sources of inhibitory inputs to WDR neurons can produce pain. SPINAL CORD NEURONS DO NOT TRANSMIT “PAIN” Clearly, some cells in the dorsal horn of the spinal cord respond to noxious stimuli, and many of these are at the origin of ascending pathways. Are they specific “pain” cells? Although some of these neurons respond exclusively to noxious stimuli, most also respond to non-noxious mechanoreceptive inputs. They may also be activated by temperature changes thus, several modalities are carried by the spinothalamic tract axons. There is no “labeled line” for pain.