Computational functions of neurons and circuits signaling injury: Relationship to pain behavior Lorne M. Mendell1 Department of Neurobiology and Behavior, State University of New York, Stony Brook, NY 11794 Edited by Donald W. Pfaff, The Rockefeller University, New York, NY, and approved November 3, 2010 (received for review August 16, 2010) The basic circuitry of the “pain pathway” mediating transmission cording from a population of small-diameter axons with proper- of information from the periphery to the brain is well known, ties of nociceptors. It is now well established that nociceptors consisting of specialized sensory fibers known as nociceptors pro- are a distinct population of sensory fibers with unique physio- jecting to specific spinal cord neurons, which in turn project on to logical, anatomical, and chemical properties. However, as we the thalamus and cerebral cortex. Here we survey some of the shall see below, activation of nociceptors can be prevented from unique properties of these circuits, such as peripheral and central causing pain, and conversely, pain is reported in situations in sensitization, and the segmental and descending modulatory con- which nociceptors are not activated. trol of synaptic transmission. We also review evidence indicating The defining characteristic of nociceptors is their high thresh- dissociation between nociceptor activity and behavioral indica- old to natural stimulation of their receptive field. This has been tions of pain. Together, these considerations point to the need investigated mostly in skin, but nociceptors exist also in muscle for a more quantitative approach to the nociceptive system, spe- and viscera. The initial work from Perl’s laboratory in the cat cifically the interactions at peripheral, spinal, and supraspinal lev- demonstrated that nociceptors could be subdivided into two els as well as between them, to more fully understand how the general groups: high-threshold mechanoreceptors whose axons activity in nociceptive neurons individually and collectively is re- conduct in the small myelinated Aδ range, and polymodal noci- lated to the pain response. ceptors sensitive to a range of modalities, including mechanical, thermal, and/or chemical, with unmyelinated C-fiber axons (6). neurotrophin | nociceptive system plasticity | gain control | gate theory | Studies using these defining characteristics as starting points have rostral ventromedial medulla revealed many additional unique characteristics of nociceptors, including their Na channel composition (9–11), their action po- his brief review surveys our current understanding of how tential configuration (12, 13), their receptors for numerous in- Tactivity in pathways activated by nociceptors contributes to the flammatory molecules (14), their transmitters (15, 16), and their experience of pain. In attempting this task we must recognize projections into the spinal cord (17, 18). certain difficulties at the outset, particularly the fact that the same stimulus might or might not be considered painful, depending on Relationship of Peripheral Nociceptors to Pain factors such as sex (1) and the genetic profile of the individual (2). The recent advances in genetic methods have offered the op- More significantly, the pain produced by a nociceptive stimulus in portunity to test the effects of removing individual molecular the same individual is influenced by situational variables, for ex- receptor classes or specific classes of nociceptors on the ability ample the level of stress, as part of the adaptive response to such to respond to nociceptive stimuli. Because of evidence that the challenges (3). To help explain this property of nociception, we TRPV1 receptor responds to noxious heat with a threshold will focus on the modifiability of these neurons and circuits be- (43 °C) that is very close to the threshold for heat pain (19), it cause this is an important determinant of the failure of activated was expected that knockout mice lacking the TRPV1 receptor nociceptive afferents to elicit a stereotyped pain response. would be unresponsive to noxious thermal stimulation. Dissoci- ated dorsal root ganglion cells from these preparations exhibited Periphery the expected loss of sensitivity to noxious heat, but the mice The concept of a neural mechanism for pain was advanced ex- themselves displayed largely normal responses to noxious heat plicitly by the 17th century philosopher René Descartes, who (20, 21). However, they exhibited a deficit in sensitization to posited a neural “channel” connecting the site of peripheral noxious agents such as carrageenan. The full explanation for these damage to the brain. The concept of the nociceptor was in- findings is not yet available. One possibility is that receptor(s) troduced more than 100 y ago by Sherrington (4), who defined it other than TRPV1 respond to thermal stimulation but are not as a sensory receptor responsive to stimuli that are potentially subject to sensitization. DRG cells expressing the unknown re- damaging to the organism; more precisely that in the skin there ceptor might be either very fragile or rare and thus unlikely to be had evolved “a special sense of its own injuries.” His focus on observed in dissociated cell culture. reflex action led him further to postulate that the action of A more recent approach has involved eliminating entire nociceptors would lead to withdrawal of the affected body part populations of nociceptors and evaluating the resulting behav- from the source of damage (5). Electrical stimulation of periph- ioral sensory loss. Cavanaugh et al. (22) have used genetic and eral nerves revealed a characteristically high threshold for the pharmacological approaches to selectively eliminate entire clas- fl fl withdrawal re ex compared with proprioceptive re exes; this was ses of nociceptors. In mice peptidergic nociceptors cells termi- interpreted as indicating that the peripheral axons responsible were relatively inexcitable (i.e., were small myelinated or un- myelinated rather than large myelinated) (6). Early attempts to This paper results from the Arthur M. Sackler Colloquium of the National Academy of record the adequate stimulus for such fibers were only partially Sciences, “Quantification of Behavior” held June 11–13, 2010, at the AAAS Building in successful, in large part because of the difficulty in recording from Washington, DC. The complete program and audio files of most presentations are available individual small fibers. This left open the possibility that pain on the NAS Web site at www.nasonline.org/quantification. results from patterned activity in sensory fibers also sensitive to Author contributions: L.M.M. analyzed previously published data and wrote the review. nonnoxious stimuli rather than activity in a special population of The author declares no conflict of interest. nociceptors. This uncertainty was resolved in the late 1960s and This article is a PNAS Direct Submission. early 1970s when Perl and collaborators (7, 8) succeeded in re- 1E-mail: [email protected]. 15596–15601 | PNAS | September 13, 2011 | vol. 108 | suppl. 3 www.pnas.org/cgi/doi/10.1073/pnas.1012195108 Downloaded by guest on September 23, 2021 nating in lamina I were selectively killed by treatment with receptors (27). This might provide an additional basis for vari- capsaicin. In companion experiments using transgenic mice, a able filtering based on the spike intervals associated with the different population of polymodal nociceptors terminating in responses of the different afferent fiber classes to specific sti- outer lamina II (lamina IIo) and expressing a unique G protein- mulus modalities. coupled receptor (MGPCR) could be selectively killed after These data suggest that certain pathways projecting from cells treatment with diphtheria toxin. Because both of these pop- in different laminae of the dorsal horn are specialized to abstract ulations are polymodal nociceptors, it was expected that elimi- certain aspects of the information coded in the discharge of nation of either class would result in a similar behavioral deficit polymodal nociceptors. This may be important in helping the involving noxious heat and high-threshold mechanical stimula- organism distinguish between the different modalities to which tion. An unexpected result was obtained, namely that eliminating the polymodal nociceptors can respond. The details of this virtually all peptidergic nociceptors terminating in lamina I re- computational achievement remain to be fully understood. duced sensitivity to thermal nociception but not to mechanical nociception. The opposite result was obtained when the Sensitization MGPCR-expressing polymodal nociceptors projecting to lamina One of the hallmarks of nociceptive pathways is sensitization in IIo were eliminated (i.e., mechanical nociceptive threshold was response to a damaging stimulus whereby the behavioral re- elevated but thermal nociception threshold was unaffected). sponse to subsequent stimuli is enhanced. In some cases nor- fi fi It is dif cult at present to give a de nitive interpretation of mally nonnociceptive stimuli elicit pain because of a decrease in these unexpected results. They suggest that the information threshold (allodynia); in others, a normally painful stimulus coded in the discharge of the nociceptors does not affect be- becomes even more painful (hyperalgesia). Two general mech- havior directly; only certain components seem to affect behavior: anisms have been identified (Fig. 1): one acting at the periphery noxious heat in the case of the TRPV1-expressing