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TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception.

ABSTRACT: In the last decade, considerable evidence as accumulated to support the development of Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists for the treatment of various chronic pain conditions. Whereas there is a widely accepted rationale for the development of TRPV1 antagonists for the treatment of various inflammatory pain conditions, their development for indications of chronic pain, where conditions of tactical, mechanical and spontaneous pain predominate, is less clear. Preclinical localization and expression studies provide a firm foundation for the use of molecules targeting TRPV1 for conditions of bone pain, osteoarthritis and neuropathic pain. Selective TRPV1 antagonists weakly attenuate tactile and mechanical hypersensivity and are partially effective for behavioral and electrophysiological endpoints that incorporate aspects of spontaneous pain. While initial studies with TRPV1 antagonist in normal human subjects indicate a loss of warm thermal perception, clinical studies assessing allelic variants suggests that TRPV1 may mediate other sensory modalities under certain conditions. The focus of this review is to summarize the current perspectives of TRPV1 for the treatment of conditions beyond those with a primary thermal sensitivity.

SUBMITTER: Brandt MR

PROVIDER: S-EPMC3763634 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception.

Brandt Michael R MR Beyer Chad E CE Stahl Stephen M SM

Pharmaceuticals (Basel, Switzerland) 20120202 2

In the last decade, considerable evidence as accumulated to support the development of Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists for the treatment of various chronic pain conditions. Whereas there is a widely accepted rationale for the development of TRPV1 antagonists for the treatment of various inflammatory pain conditions, their development for indications of chronic pain, where conditions of tactical, mechanical and spontaneous pain predominate, is less clear. Preclinical ...[more]

PMID: 24288084

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Project description:BackgroundSerotonin (5-HT) is highly involved in pain regulation and serotonin-1A (5-HT1A) receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A) may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP) rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities.MethodsFourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C-49°C). Nociceptive-flexion reflex (NFR) thresholds were also assessed.ResultsVolunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged.Conclusion/significanceTo the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a 'hypo- to hyperalgesic' response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain pathologies. Further investigations are therefore warranted.

Project description:The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We have recently reported that chronic pain is associated with amplified activity of PB neurons in a rat model of neuropathic pain. Here we demonstrate that similar activity amplification occurs in mice, and that this is related to suppressed inhibition to lateral parabrachial (LPB) neurons from the CeA in animals of either sex. Animals with pain after chronic constriction injury of the infraorbital nerve (CCI-Pain) displayed higher spontaneous and evoked activity in PB neurons, and a dramatic increase in after-discharges, responses that far outlast the stimulus, compared with controls. LPB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that, in both rats and mice, LPB contains few GABAergic neurons, and that most of its GABAergic inputs arise from CeA. These CeA GABA neurons express dynorphin, somatostatin, and/or corticotropin releasing hormone. We find that the efficacy of this CeA-LPB pathway is suppressed in chronic pain. Further, optogenetically stimulating this pathway suppresses acute pain, and inhibiting it, in naive animals, evokes pain behaviors. These findings demonstrate that the CeA-LPB pathway is critically involved in pain regulation, and in the pathogenesis of chronic pain.SIGNIFICANCE STATEMENT We describe a novel pathway, consisting of inhibition by dynorphin, somatostatin, and corticotropin-releasing hormone-expressing neurons in the CeA that project to the parabrachial nucleus. We show that this pathway regulates the activity of pain-related neurons in parabrachial nucleus, and that, in chronic pain, this inhibitory pathway is suppressed, and that this suppression is causally related to pain perception. We propose that this amygdalo-parabrachial pathway is a key regulator of both chronic and acute pain, and a novel target for pain relief.

Project description:AIM: The main aim of this study was to assess if the perception of thermal pain thresholds is associated with genetically inferred levels of expression of the 5-HT transporter (5-HTT). Additionally, the perception of the so-called thermal grill illusion (TGI) was assessed. Forty-four healthy individuals (27 females, 17 males) were selected a-priori based on their 5-HTTLPR/rs25531 ('tri-allelic 5-HTTLPR') genotype, with inferred high or low 5-HTT expression. Thresholds for heat- and cold-pain were determined along with the sensory and affective dimensions of the TGI. RESULTS: Thresholds to heat- and cold-pain correlated strongly (rho ?=?-0.58, p<0.001). Individuals in the low 5-HTT-expressing group were significantly less sensitive to heat-pain (p?=?0.02) and cold-pain (p?=?0.03), compared to the high-expressing group. A significant gender-by-genotype interaction also emerged for cold-pain perception (p?=?0.02); low 5-HTT-expressing females were less sensitive. The TGI was rated as significantly more unpleasant (affective-motivational dimension) than painful (sensory-discriminatory dimension), (p<0.001). Females in the low 5-HTT expressing group rated the TGI as significantly less unpleasant than high 5-HTT expressing females (p<0.05), with no such differences among men. CONCLUSION/SIGNIFICANCE: We demonstrate an association between inferred low 5-HTT expression and elevated thresholds to thermal pain in healthy non-depressed individuals. Despite the fact that reduced 5-HTT expression is a risk factor for chronic pain we found it to be related to hypoalgesia for threshold thermal pain. Low 5-HTT expression is, however, also a risk factor for depression where thermal insensitivity is often seen. Our results may thus contribute to a better understanding of the molecular underpinnings of such paradoxical hypoalgesia. The results point to a differential regulation of thermoafferent-information along the neuraxis on the basis of 5-HTT expression and gender. The TGI, suggested to rely on the central integration of thermoafferent-information, may prove a valuable tool in probing the affective-motivational dimension of these putative mechanisms.

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TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception.

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TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception.

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