### A. Overview

Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface receptors termed purine receptors. In this review particular emphasis is placed on the discrepancy between the

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Receptors for Purines and Pyrimidines

https://www.cell.com/cell/pdf/S0092-8674(09)01243-4.pdf

Cellular and Molecular Mechanisms of Pain

Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.

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Central sensitization: implications for the diagnosis and treatment of pain.

http://www.columbia.edu/cu/biology/courses/w3004/recitation7.pdf

The Cloned Capsaicin Receptor Integrates Multiple Pain-Producing Stimuli

The prevalence and cost of chronic pain is a major physical and mental health care problem in the United States today. As a result, there has been a recent explosion of research on chronic pain, with significant advances in better understanding its etiology, assessment, and treatment. The purpose of the present article is to provide a review of the most noteworthy developments in the field. The biopsychosocial model is now widely accepted as the most heuristic approach to chronic pain. With this model in mind, a review of the basic neuroscience processes of pain (the bio part of biopsychosocial), as well as the psychosocial factors, is presented. This spans research on how psychological and social factors can interact with brain processes to influence health and illness as well as on the development of new technologies, such as brain imaging, that provide new insights into brain-pain mechanisms.

/pdf/the-biopsychosocial-approach-to-chronic-pain-scientific-1047fjbjjh.pdf

The Biopsychosocial Approach to Chronic Pain: Scientific Advances and Future Directions

the concept that sense organs of the skin with unmyelinated (C) fibers have widely varying functional characteristics. In the mammal, a large proportion of such sensory units are excited by gentle mechanical stimuli (8, 16, 34) and by transient cooling (9). Others are described as responding best to small temperature changes (13, 18) and some are reported to have elevated thresholds for various or all stimuli (14, 15, 18, 32). Studies proposing large and important differences between various afferent units with C fibers have drawn conclusions from a small or highly selected population and no view has been provided of the way in which these differences fit into the spectrum presented by the sensory structures from a given skin region. Such information seems essential for the understanding of somatic sensation inasmuch as unmyelinated fibers far outnumber myelinated fibers in the afferent nerves from the skin. In particular, unmyelinated afferent fibers are generally agreed to have some causal relation to pain and its associated reactions (3, 6, 7, 25). A crucial issue in hypotheses correlating afferent activity to pain is whether the underlying mechanisms are set off by impulses from sensory structures responding only to noxious stimuli (i.e., intense enough to threaten or (cause tissue damage) or whether they are triggered by special patterns of discharge from nonspecific afferent units (25). In an attempt to learn more about the range of behavior associated with the terminals of cutaneous C fibers, we surveyed a number of randomly sele,cted units for responses to a variety of graded stimuli. The results point out that a large proportion of

Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli.

Single primary afferent myelinated fibers from cutaneous receptors of cat and monkey were functionally identified by recording from the spinal cord with micropipettes filled with horseradish peroxidase (HRP). Relatively slowly conducting fibers (less than 40 m/sec) from high threshold mechanoreceptors (mechanical nociceptors) and two types of low threshold mechanoreceptor (D-hair and field) were selected for staining. Iontophoresis of the HRP and subsequent histochemical reaction stained the axons recorded from and their collaterals, including terminations, for several millimeters. The termination patterns in the two species proved essentially identical. Ipsilaterally, the mechanical nociceptor fibers terminated principally in the dorsal horn's marginal zone and in the ventral parts of the nucleus proprius (lamina V in the cat). Some of these nociceptors also had terminals in the midline just dorsal to the central canal, contralaterally in the marginal zone, and at the base of the opposite nucleus proprius. In contrast, the D-hair primary afferent axons terminated in the dorsal part of the nucleus proprius overlapping into the innermost portion of the substantia gelatinosa. The field receptor fibers terminated predominantly in the middle part of the nucleus proprius. These results suggest that there is a highly specialized central projection of primary afferent endings which is related to sensory function and not to fiber diameter. The marginal zone and most dorsal parts of the substantia gelatinosa receive direct projections from cutaneous nociceptors but do not have direct input from cutaneous receptors transmitting activity initiated by innocuous stimulation.

Spinal termination of functionally identified primary afferent neurons with slowly conducting myelinated fibers.

HIGH-THRESHOLD MECHANORECEPTORS and their centrally projecting myelinated fibers make up a functionally distinct group of cutaneous sensory units that have been suggested as part of the afferent apparatus for pain resulting from mechanical damage to the skin (3, 17). The argument for their relation to pain was based on two points: 1) the ability of such afferent elements, unique among those with medullated fibers, to provide signals differentiating noxious from innocuous mechanical events affecting the skin; and 2) the well-established correlation between pain and activity in thin myelinated afferent fibers

Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn.

Although information from sense organs is used by all animals, only man can verbally report his sensory experience. A brief consideration of these experiences may be useful in providing insight into cutaneous sensory mechanisms. Nonnoxious deformation of the human skin with a stimulator having a small surface area (2–3 mm2) evokes sensations usually referred to as “touch”. If the stimulator remains stationary, the sensation fades. Movement of the stimulator perpendicular to the skin produces changes in the sensory process which allow even rapidly repeated stimuli (e.g. 500 Hz) to be distinguished from stationary ones. When larger stimulators are used, some appreciation of texture can be obtained, and this is enhanced by movement of the stimulating surface across the skin. A smooth stimulator or an insect moving slowly and gently over the skin evokes distinctive sensations usually referred to as “tickle”. A sharp object such as a pin lightly pressed against certain points in the skin leads to an unpleasant experience which differs from touch but is equivocally painful; when the pin is pressed against the skin more firmly it usually elicits pain. Thus, sensations induced by mechanical events can be diverse. Moreover, common experience indicates that they may occur with greater or lesser intensity. On the other hand, neurophysiological experiments defining the properties of cutaneous sense organs have most often been done on animals other than man.

Cutaneous Mechanoreceptors and Nociceptors

The mechanisms by which peripheral nerve injuries sometimes lead to causalgia, aberrant burning pain peripheral to the site of nerve damage, are uncertain, although the sympathetic nervous system is known to be involved. Whether such syndromes could be the result of the development of responsiveness by some cutaneous pain receptors (C-fiber nociceptors) to sympathetic efferent activity as a consequence of the nerve injury was tested in an animal model. After nerve damage but not in its absence, sympathetic stimulation and norepinephrine were excitatory for a subset of skin C-fiber nociceptors and enhanced the responsiveness of these nociceptors to tissue-damaging stimulation. These effects were demonstratable within days after nerve lesions, occurred at the cutaneous receptive terminal region, were manifest in sensory fibers that had not degenerated after the injury, and were mediated by alpha 2-adrenergic-like receptors.

https://science.sciencemag.org/content/sci/251/5001/1608.full.pdf

Edward R. Perl

Papers

Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli.

Spinal termination of functionally identified primary afferent neurons with slowly conducting myelinated fibers.

Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn.

Cutaneous Mechanoreceptors and Nociceptors

Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury