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Hot Peppers and Pain

1998; Cell Press; Volume: 21; Issue: 4 Linguagem: Inglês

10.1016/s0896-6273(00)80575-9

1097-4199

Patrick W. Mantyh, Stephen P. Hunt,

Pain Mechanisms and Treatments

Capsaicin, the main pungent ingredient in hot chili peppers, has been used for centuries as a spice. Aside for its expanding culinary use, in the past 2 decades capsaicin has also provided remarkable insight not only into the neurobiology of primary afferent nociceptors but also into new treatments for chronic pain. The major reason that capsaicin has been so useful is its remarkable cellular specificity. Nearly all of the actions of capsaicin can be attributed to a single mechanism—activation of a nonspecific cation channel in a population of primary afferent sensory neurons known as C fibers, 80% of which are polymodal nociceptors. Polymodal nociceptors are activated by noxious thermal, mechanical, or chemical stimuli and as such are thought to be intimately involved in the generation and maintenance of chronic pain. The belief among many pain researchers is that insight into the cellular and molecular mechanisms that underlie transducer functions in nociceptors will lead to an increased understanding of the peripheral events involved in the generation and/or maintenance of chronic pain (8Levine J.D. Neuron. 1998; 20: 649-654Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). This belief is buttressed by the finding that repeated application of capsaicin induces desensitization of nociceptors and that this treatment can ameliorate several chronic pain states, including those arising from herpes zoster and oral cancer (6Maggi C.A. Life Sci. 1992; 51: 1777-1781Crossref PubMed Scopus (50) Google Scholar). To understand the action and cellular specificity of capsaicin, a key question was to define whether capsaicin interacted with one or more receptors and, if so, to determine the structure and normal function of this receptor. Numerous studies demonstrated that capsaicin and capsaicin analogs had a well-defined structure–activity relationship. On the basis of these studies, the competitive antagonist of capsaicin known as capsazepine was developed (1Bevan S. Hothi S. Hughes G. James I.F. Rang H.P. Shah K. Walpole C.S.J. Br. J. Pharmacol. 1992; 107: 5444-5552Crossref Scopus (523) Google Scholar), and resiniferatoxin, a naturally occurring ultrapotent structural analog of capsaicin, was used to define a ligand binding site in sensory neurons (10Szallasi A. Gen. Pharmacol. 1994; 25: 223-243Crossref PubMed Scopus (192) Google Scholar). While this data suggested that capsaicin did exert its actions via a receptor, additional data suggested that there was more than one type of capsaicin receptor. To emphasize the possible heterogeneity of receptors that interact with capsaicin, the term vallinoid receptor was coined (10Szallasi A. Gen. Pharmacol. 1994; 25: 223-243Crossref PubMed Scopus (192) Google Scholar). Despite the enormous interest surrounding capsaicin, it was not until 1997 that a capsaicin receptor was cloned. In this groundbreaking work, Julius and his colleagues expression cloned the capsaicin receptor (2Caterina M.J. Schumacher M.A. Tominaga M. Rosen T.A. Levine J.D. Julius D. Nature. 1997; 389: 816-824Crossref PubMed Scopus (6529) Google Scholar), which they named the vallinoid receptor 1 (VR1), predicting as the name implies several more as yet undescribed receptor genes. This receptor was a nonselective cation channel that is structurally related to members of the transient receptor potential family of ion channels. Capsaicin and heat in the noxious range activated the VR1, although it was not clear whether heat was activating the VR1 directly or through other thermally sensitive molecules. This study also generated a host of other questions regarding the endogenous ligand for the VR1: its physiological function, which neurons express the VR1 protein, and whether there are other VRs in sensory neurons or other areas of the brain. In a recent paper (11Tominaga M. Caterina M.J. Malmberg A.B. Rosen T.A. Gilbert H. Skinner K. Raumann B.E. Basbaum A.I. Julius D. Neuron. 1998; 21: 531-543Abstract Full Text Full Text PDF PubMed Scopus (2439) Google Scholar) in the September issue of Neuron, the combined efforts of the Julius and Basbaum labs elegantly address several of these important questions. Using excised membrane patches, they show that heat gates VR1 directly and that an increase in protons, at levels that occur at sites of inflammation, infection, or ischemia, activates VR1 at room temperature. In light of this data, they propose a model that highlights the notion that vallinoids, heat, and protons act in concert to regulate VR1 activity and that the effects of any one stimulus cannot be considered in isolation. Thus, whether thermal or chemical stimuli will be important in activating VR1 in vivo will likely vary with the site and degree of the injury. As an example, they suggest that whereas both temperature and pH would be expected to play a role in VR1 activation in skin, in areas such as the viscera where temperature is more constant, pH and not temperature will play a more important role in VR1 activation. The authors then go on to suggest that VR1 functions as an integrator of multiple pain-producing stimuli. What is particularly exciting and intellectually satisfying about this work is that it begins to unite the often disparate findings regarding the actions of capsaicin and its analogs into a comprehensible whole. This paper also addresses the types of sensory neurons that express the VR1 protein. In the past several years, a hypothesis has emerged that suggests that polymodal nociceptors can be divided into at least two large groups (5Hunt, S.P., Mantyh, P.W., and Priestly, J.V. (1993). In Sensory Neurons: Diversity, Development, and Plasticity, S.A. Scott, ed. (New York: Oxford University Press), pp. 60–76.Google Scholar, 9Snider W.D. McMahon S.B. Neuron. 1998; 20: 629-632Abstract Full Text Full Text PDF PubMed Scopus (704) Google Scholar). One population contains peptides such as substance P and calcitonin gene–related peptide, expresses the trkA receptor, and is responsive to nerve growth factor (NGF); a second population is trkA negative and does not contain peptides but can be identified from their IB4 lectin binding sites and the expression of the P2X3 receptor. The latter population of neurons loses its trkA receptors 3 weeks after birth but expresses ret receptor components and responds to glial cell line–derived neurotrophic factor (GDNF). It has also been shown that these two populations of sensory neurons preferentially terminate in different parts of the spinal cord. Whereas the peptide/trkA fibers terminate in superficial laminae of the dorsal horn, particularly laminae I and II outer, the IB4/ret population terminates deeper in a narrow band within lamina II inner in association with a layer of neurons expressing high levels of protein kinase C γ (PKCγ). A functional correlation has also been made between the two types of sensory neurons. Loss of the PKCγ gene using homologous recombination in mice prevents the development of neuropathic pain following partial nerve section (7Malmberg A.B. Chen C. Tonegawa S. Basbaum A.I. Science. 1997; 278: 279-283Crossref PubMed Scopus (565) Google Scholar), while experimental inflammation of the hind paw in rats and mice results in an increased expression of substance P in the peptide/trkA neurons. This has led to the suggestion that chronic inflammatory pain is mediated largely by the peptide/trkA-containing sensory neurons that terminate in superficial laminae, while neuropathic pain resulting from peripheral nerve damage is mediated by the IB4/ret population that terminates in the deeper regions of lamina II (9Snider W.D. McMahon S.B. Neuron. 1998; 20: 629-632Abstract Full Text Full Text PDF PubMed Scopus (704) Google Scholar). To determine which sensory neurons express the VR1 protein, antibodies were generated to the predicted carboxyl terminus of VR1, and an immunohistochemical analysis was performed. The results are surprising. Staining of the sensory ganglion revealed that about 80% of both IB4/ret- and peptide/trkA-containing sensory neurons express VR1 protein-like immunoreactivity. In other words, there appears to be a small but substantial population of sensory neurons that do not express the VR1 but which previously have been shown to be sensitive to capsaicin. This data, along with binding studies with tritiated resiniferatoxin, suggests that there are additional vanilloid receptors. The immunohistochemical analysis also revealed an unexpected heterogeneity in the IB4/ret population of sensory neurons that terminates in the inner portion of lamina II. It has previously been shown that the medial and lateral regions of the dorsal horn of the spinal cord represent distal and proximal parts of the hindlimb, respectively (3Devor M. Claman D. Brain Res. 1980; 190: 17-28Crossref PubMed Scopus (145) Google Scholar). What is unique in the present report is that whereas the IB4/ret population that terminates in the medial aspect of lamina II inner shows colocalization with VR1, the IB4/ret population that terminates in the lateral aspect of lamina II inner shows virtually no colocalization with VR1. This data suggests that either the IB4/ret populations which innervate the distal aspects of a limb express the VR1, whereas those that express the proximal aspect of the limb do not, or that there is differential transport of the VR1 receptor protein to the spinal cord in these two populations of sensory neurons. There is a precedent for differential transport of a receptor in primary afferents: the neuropeptide Y Y1 receptor that is expressed in sensory neurons is found in the cell bodies but rarely in the axons that terminate in the spinal cord (12Zhang X. Bao L. Xu Z.Q. Kopp J. Arvidsson U. Elde R. Hokfelt T. Proc. Natl. Acad. Sci. USA. 1994; 91: 11738-11742Crossref PubMed Scopus (121) Google Scholar). Also, Robert Elde’s lab has suggested that the synthesis and trafficking of a receptor and neurotransmitter can be coregulated in sensory neurons. Thus, disruption of the preprotachykinin gene inhibits the translation of δ opiate receptor—a protein normally coexisting in the same synaptic vesicles as substance P (4Dray A. Rang H. Trends Neurosci. 1998; 21: 315-317Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Thus, the expression of VR1 could potentially be regulated at the transcriptional, translational, or axoplasmic transport level. Differential regulation of transport would result in modified terminal sensitivity within discrete populations of sensory neurons. Why do pain researchers find this work so interesting? The majority of therapies used today for the treatment of chronic pain (opiates, aspirin, and codeine) have been utilized for over a century and have significant side effects, especially with long-term use. One of the most promising avenues for discovering new molecules to treat chronic pain is to understand the molecular and cellular mechanisms that underlie transducer function in primary afferent nociceptors. The beauty of the present work is that it begins to provide a cellular and molecular framework for understanding the vast and often provocative literature on the biological actions of capsaicin. It would be highly surprising if future work on capsaicin and VR1 does not contribute significantly to our knowledge of sensory transducer function and ultimately to the development of new therapies for treating persistent pain.