Alleviation of mechanical and thermal allodynia by CGRP8-37 in a rodent model of chronic central pain

Abstract

CGRP(8-37) is a truncated version of calcitonin gene-related peptide (CGRP) that binds to the CGRP receptor with similar affinity but does not activate the receptor and is a highly selective CGRP receptor antagonist. CGRP and activation of its receptor appear to play a role in peripheral inflammatory and neuropathic models of pain although there is considerable controversy. The aim of this study was to examine possible anti-nociceptive effects of CGRP(8-37) on a model of chronic central neuropathic pain known to develop weeks after spinal hemisection. Adult male Sprague-Dawley rats were given a spinal hemisection (N=34) or a sham surgery (N=10) at the T13 spinal segment. An externally accessible PE-10 intrathecal catheter that terminated at T13 was used for drug delivery. Animals were allowed to recover for 4 weeks at which time the hemisected animals displayed mechanical and thermal allodynia bilaterally, in both forelimbs and hindlimbs. CGRP(8-37) was delivered just prior to a testing session in 1, 5, 10, or 50 nM doses in artificial cerebral spinal fluid in 10 microl volumes. CGRP(8-37) was effective in alleviating mechanical and thermal allodynia in a dose-dependent manner (P<0.05). The 50 nM dose was most efficacious for both forelimb and hindlimb responses (P<0.05). The period of efficacy was 10 min to onset for a duration of 20 min. Post-drug washout responses were not statistically significant compared to pre-drug responses. The sham control groups demonstrated no statistically significant difference at any dose of CGRP(8-37) when compared to pre-surgical baseline values. In conclusion, CGRP(8-37) is effective in abolishing mechanical and thermal allodynia produced by spinal hemisection. Consequently, the CGRP receptor may play a role in chronic central neuropathic pain and offers a novel therapeutic approach to managing chronic central pain.

Ablation and Regeneration of Peripheral and Central TRPV1 Expressing Nerve Terminals and the Consequence of Nociception

“…Neuronal activity increases endovanilloid levels during chronic pain conditions, which are synthesized and released on demand [42][43][44][45][46]. Studies have shown that blocking neuropeptide release alleviates inflammatory [47][48][49] and neuropathic pain [50]. Drugs that inhibit activation of glia have been shown to alleviate chronic pain [51].…”

Current and prospective pharmacological targets in relation to antimigraine action

“…The receptors of both estrogen and progesterone alter receptor expression and release, as well as synthesis of various neurotransmitters and hormones. For example, CGRP, a facilitator of pain transmission and a potent vasodilator (Bennett et al 2000;Powell et al 2000), neuropeptide Y, a regulator of inflammation and central nociception (Silva et al 2002), as well as the neurotransmitters glutamate (Zhang and Bhavnani 2005), and 5-HT ) have been reported to be genomically modulated by sex steroids. Remarkably, progesterone can act in a synergistic, antagonistic, or neutral manner compared to the effects of estrogens (Attali et al 1997;Becker and Rudick 1999;Dluzen and Ramírez 1989;Fernández-Ruíz et al 1990;Hernández et al 1991).…”

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

“…The neuropeptide calcitonin gene-related peptide (CGRP) is found in a subset of polymodal nociceptive afferents that are activated by a variety of noxious stimuli, including heat (Caterina et al, 1999(Caterina et al, , 2000Davis et al, 2000). CGRP release from these afferents in the dorsal horn enhances thermal and mechanical nociceptive sensitivity (Bennett et al, 2000;Sun et al, 2003). In peripheral tissues, CGRP released from perivascular afferents contributes to the development and maintenance of neurogenic inflammation Gamse and Saria, 1986).…”