Elsevier

Neuroscience

Volume 86, Issue 2, 1 June 1998, Pages 619-626
Neuroscience

A capsaicin-receptor antagonist, capsazepine, reduces inflammation-induced hyperalgesic responses in the rat: evidence for an endogenous capsaicin-like substance

https://doi.org/10.1016/S0306-4522(98)00012-8Get rights and content

Abstract

In the present study, the presence of an endogenous capsaicin-like substance and the role of capsaicin receptors in nociception during inflammation were assessed using Fos immunohistochemistry and the paw-withdrawal test in rats. Intradermal injection of carrageenan in the hind-paw produced inflammation in the foot pad, increased the number of cells exhibiting Fos-like immunoreactivity in the dorsal horn of the spinal cord, and decreased the paw-withdrawal latency. Intradermal injection of capsazepine, a capsaicin-receptor antagonist, significantly reduced the number of cells exhibiting Fos-like immunoreactivity, significantly increased the paw-withdrawal latency, but did not decrease inflammation induced by carrageenan injection. Intradermal injection of capsaicin or formalin also increased Fos-positive neurons. Capsaicin- or formalin-induced Fos expression was reduced in both cases by pretreatment of capsazepine, but to a much lesser extent for formalin.

The capsazepine inhibition of carrageenan inflammation-induced hyperalgesic responses strongly suggests that an endogenous capsaicin-like substance is released in inflamed tissues and produces nociceptive neural impulses by acting on capsaicin receptors present on sensory neurons. Furthermore, our results indicate that capsaicin receptors take part only in generating nociceptive signals in sensory neurons, but not in activating the inflammation-promoting cells.

Section snippets

Experimental procedures

Inflammation was induced in male Sprague–Dawley rats weighing 250–350 g by intradermal injection of 6 mg carrageenan (λ-carrageenan, Sigma, St Louis, MO, U.S.A.) dissolved in 150 μl, 0.9% NaCl in the foot pads of the hind-paws. In another group of animals, varying doses of capsazepine (0.05, 0.3, 0.6, or 1.5 mg in 150 μl of vehicle; Research Biochemicals International, Natick, MA, U.S.A.) were injected in the left foot, and vehicle (saline containing 50% dimethylsulphoxide) for capsazepine was

Effect of capsazepine on carrageenan-induced Fos-like immunoreactivity

As shown in Fig. 1, intradermal injection of carrageenan (6 mg in 150 μl saline) resulted in an increased expression of Fos-LI in neurons in the ipsilateral dorsal horn of the spinal cord. There were many cells exhibiting Fos-LI clustering in the superficial layer (lamina I and II) of the dorsal horn after carrageenan injection (Fig. 1A, B). Many cells exhibiting Fos-LI were also found in the deep laminae of the dorsal horn, primarily in lamina V, VI, and X and occasionally in lamina III and IV.

Discussion

Because pain and pain-associated reflexes are evoked by capsaicin, it is widely accepted that capsaicin receptors have a role in nociceptive neural transmission, however such a role has not been tested previously and the presence of an endogenous ligand at these receptors has not been previously demonstrated. In the present study, we showed that carrageenan inflammation-induced hyperalgesic responses were reduced by the capsaicin receptor antagonist, capsazepine. This result clearly indicates

Conclusions

In summary, we have observed that capsazepine reduced the hyperalgesic responses evoked during carrageenan-induced inflammation, without affecting the inflammation itself. Thus, the present study presents clear evidence for the presence of an endogenous capsaicin-like substance that mediates the pain associated with inflammation. Identification and characterization of this substance and the associated receptor/channels may aid in the development of more specific analgesics.

Acknowledgements

This work was supported by the Ministry of Health and Welfare of Korea and by a grant from the Korea Science and Engineering Foundation through the Research Center for New Drug Development.

References (41)

  • P. Marchettini et al.

    Pain from excitation of identified muscle nociceptors in humans

    Brain Res.

    (1996)
  • S.J. Marsh et al.

    The mechanism of action of capsaicin on sensory c-type neurons and their axons in vitro

    Neuroscience

    (1987)
  • K.M. Park et al.

    Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects

    Pain

    (1995)
  • A. Rueff et al.

    Sensitization of peripheral afferent fibers in the in vitro neonatal rat spinal cord-tail by bradykinin and prostaglandins

    Neuroscience

    (1993)
  • M. Schmelz et al.

    Topical acetylsalicylate attenuates capsaicin induced pain, flare and allodynia but not thermal hyperalgesia

    Neurosci. Lett.

    (1996)
  • D.A. Simone et al.

    Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin

    Pain

    (1989)
  • A. Szallasi et al.

    Resiniferitoxin, a phorbol-related diterpene acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper

    Neuroscience

    (1989)
  • A. Szallasi et al.

    Vanilloid (capsaicin) receptors in the rat: distribution in the brain, regional differences in the spinal cord, axonal transport to the periphery, and depletion by systemic vanilloid treatment

    Brain Res.

    (1995)
  • L.R. Watkins et al.

    Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states

    Pain

    (1995)
  • S. Williams et al.

    Changing patterns of c-fos induction in spinal neurons following thermal cutaneous stimulation in the rat

    Neuroscience

    (1990)
  • Cited by (101)

    • Participation of peripheral TRPV1, TRPV4, TRPA1 and ASIC in a magnesium sulfate-induced local pain model in rat

      2016, Neuroscience
      Citation Excerpt :

      We observed that when capsazepine is administered intraplantarily, mechanical hyperalgesia is reduced only in the ipsilateral, but not in the contralateral paw, thus revealing its local effect. Our results are in agreement with literature data showing that locally administered capsazepine reduces mechanical and thermal inflammatory hyperalgesia (Kwak et al., 1998) and pain-related behavior (Santos and Calixto, 1997; Sakurada et al., 2003; Tang et al., 2007; Potenzieri et al., 2009). The reasons for the large range of doses mentioned in the literature may be due to many factors related to the experimental model, such as species differences (Walker et al., 2003), the type of fiber examined (thermal perception requires relatively high doses), pain models (neuropathic, inflammatory pain), and pro-inflammatory substances.

    • Anti-inflammatory effects of Bryophyllum pinnatum (Lam.) Oken ethanol extract in acute and chronic cutaneous inflammation

      2014, Journal of Ethnopharmacology
      Citation Excerpt :

      Our results showed that EEBP inhibited the phenol-induced ear edema, similarly to dexamethasone, suggesting a possible use in the treatment of contact dermatitis (Fig. 3B). When applied on the skin, capsaicin promotes a cutaneous neurogenic inflammation with a maximum peak of edema formation achieved 30 min after application (Kwak et al., 1998). Capsaicin acts as an agonist of vanilloid receptor 1 (TRPV1) that promotes the release of substance P (SP) and calcitonin gene related peptide (CGRP), which elicits inflammation responses by releasing pro-inflammatory mediators, such as bradykinin (BK), histamine, 5-HT and PGs (Szolcsányi, 2004; Zegarska et al., 2006).

    • The TRPV1 ion channel antagonist capsazepine inhibits osteoclast and osteoblast differentiation in vitro and ovariectomy induced bone loss in vivo

      2010, Bone
      Citation Excerpt :

      Numerous studies have demonstrated the ability of capsazepine to block capsaicin induced calcium uptake, acting primarily on TRPV1 ion channels in vitro[10–14]. In experimental animal models, capsazepine reduces hyperalgesia induced by mechanical stimuli, capsaicin or carrageenan injection or in animal models of osteosarcoma [15–19]. However, in response to reports of capsazepine displaying species-dependent efficacies in rodent models of hyperalgesia and chronic pain, a new generation of selective TRPV1 ligands has been developed.

    • The Role of the Vanilloid and Related Receptors in Nociceptor Function and Neuroimmune Regulation

      2009, NeuroImmune Biology
      Citation Excerpt :

      Second, anti-TRPV1 antiserum ameliorates thermal allodynia in diabetic mice [90]. Third, TRPV1 antagonists such as capsazepine exert beneficial effects in animal models of neuropathic pain [23]. Primary afferent unmyelinated fibers possessing TRPV1 modulate the inflammatory response to injury by initiating the release of a cascade of proinflammatory mediators, known as neurogenic inflammation.

    • Effects of Bradykinin on Nociceptors

      2009, NeuroImmune Biology
    View all citing articles on Scopus
    View full text