Contributions of calcitonin gene-related peptide in ischemia, inflammation and nociception
Author: Brodda Jansen, Gunilla
Date: 1996-03-15
Location: Fysiologiska institutionens föreläsningssal
Time: 9.00
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.
Issue date: 1996-02-23
Publication year: 1996
ISBN: 91-628-1898-8
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