Journal of Neuroscience, Vol 16, 2342-2351, Copyright © 1996 by Society for Neuroscience
A calcitonin gene-related peptide receptor antagonist prevents the development of tolerance to spinal morphine analgesia
DP Menard, D van Rossum, S Kar, S St Pierre, M Sutak, K Jhamandas and R Quirion
Douglas Hospital Research Center, McGill University, Verdun, Quebec, Canada.
Tolerance to morphine analgesia is believed to result from a neuronal
adaptation produced by continuous drug administration, although the precise
mechanisms involved have yet to be established. Recently, we reported
selective alterations in rat spinal calcitonin gene-related peptide (CGRP)
markers in morphine-tolerant animals. In fact, increases in CGRP-like
immunostaining and decrements in specific [125]hCGRP binding in the
superficial laminae of the dorsal horn were correlated with the development
of tolerance to the spinal antinociceptive action of morphine. Other
spinally located peptides such as substance P, galanin, and neuropeptide Y
were unaffected. Thus, the major goal of the present study was to
investigate whether the development of tolerance to spinally infused
morphine could be modulated by the blockade of dorsal horn CGRP receptors
using the potent CGRP antagonist hCGRP(8-37). Indeed, cotreatments with
hCGRP(8-37) prevented, in a dose- dependent manner, the development of
tolerance to morphine-induced analgesia in both the rat
tail-flick/tail-immersion and paw-pressure tests. Moreover, alterations in
spinal CGRP markers seen in morphine- tolerant animals were not observed
after a coadministration of morphine and hCGRP(8-37). These results
demonstrate the existence of specific interaction between CGRP and the
development of tolerance to the spinal antinociceptive effects of morphine.
They also suggest that CGRP receptor antagonists could become useful
adjuncts in the treatment of pain and tolerance to the antinociceptive
effects of morphine.
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