Contributions of calcitonin gene-related peptide in ischemia, inflammation and nociception

Abstract

The sensory neuropeptide Calcitonin gene-related peptide (CGRP) is a very potent vaso- dilator with a wide distribution in peripheral sensory nerves, often co-stored with sub- stance P. In the present study, the effects of CGRP in different models of ischemia, inflammation and nociception were examined.

Calcitonin gene-related peptide, but not substance P (SP), was found to inhibit edema-promoting actions of inflammatory mediators (histamine, leukotrine B4, 5-hydroxytryptamine, 5-HT) in vivo in the hamster cheek pouch, human skin, and rat paw. Accordingly, the CGRP antagonist CGRP8-37 enhanced 5-HT-induced edema in the rat paw. The effect of CGRP in the cheek pouch was present in the low nanomolar dose range, and it was mimicked by activation of sensory nerves with capsaicin which caused release of endogenous CGRP-like immunoreactivity (-LI). The findings suggest that the release of CGRP following sensory nerve activation during inflammatory pro- cesses may play an anti-inflammatory role.

Activation of sensory nerves and local injection of CGRP in surgical skin flaps in rats significantly increased blood flow and flap survival. Intraperitoneal pretreatment with very low doses of CGRP dose-dependently increased the survival of flaps. Moreover, CGRP significantly reduced the marked surgery-induced accumulation of myeloperoxi- dase (a marker for neutrophil recruitment) in the flaps. In addition, it was found that inhibition of mast cell activation with disodium cromoglycate significantly improved the flap survival, and that CGRP had the capacity to inhibit mast cell mediator release. These findings indicate that the beneficial effect of CGRP on flap survival may involve inhibition of surgically induced neutrophil recruitment, possibly via a mechanism invol- ving inhibition of mast cell function.

The effect of peripheral and intrathecal administration of CGRP and the CGRP anta- gonist CGRP8-37 on nociception was studied. Subplantar injection of CGRP or CGRP8-37 into the rat hind paw did not affect the withdrawal response to nociceptive thermal stimuli or mechanical stimulation. Injection of s-HT into one hindpaw redu- ced withdrawal responses, a reduction which was not affected by pretreatment with CGRP or CGRP8 37. On the other hand, intrathecal administration of CGRP8-37 increased hind paw withdrawal latency to noxious thermal and mechanical stimulation. This effect was more pronounced in intact rats than in rats with unilateral carrageenan- induced hind paw inflammation. The effect of intrathecal CGRP8 37 on withdrawal responses was partly reversed by intrathecal injection of naloxon, indicating that opioids modulate the effect of CGRP in the spinal cord. The unilateral injection of car- rageenan was found to cause a bilateral decrease in withdrawal response, and increased CGRP-LI in the perfusate of both hind paws as well as in the cerebrospinal fluid after 24 h.

Taken together, the results indicate that CGRP modulates nociception via central but not peripheral mechanisms. Moreover, CGRP has anti-inflammatory actions which may help explain the beneficial effects seen on survival of surgical flaps.