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Blockade and reversal of spinal morphine tolerance by peptide and non‐peptide calcitonin gene‐related peptide receptor antagonists

Blockade and reversal of spinal morphine tolerance by peptide and non‐peptide calcitonin... This study examined the effects of the peptide CGRP receptor antagonist CGRP8‐37 and the newly‐developed non‐peptide CGRP receptor antagonist BIBN4096BS for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. Repeated administration of intrathecal morphine (15 μg), once daily, produced a progressive decline of antinociceptive effect and an increase in the ED50 value in the tailflick and paw pressure tests. Co‐administration of CGRP8‐37 (4 μg) or BIBN4096BS (0.05, 0.1 μg) with morphine (15 μg) prevented the decline of antinociceptive effect and increase in ED50 value in the tailflick test. Intrathecal administration of the CGRP receptor antagonists did not alter the baseline responses in either tests. Acute CGRP8‐37 also did not potentiate the acute actions of spinal morphine. In animals rendered tolerant to intrathecal morphine, subsequent administration of CGRP8‐37 (4 μg) with morphine (15 μg) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the reversal of tolerance. Animals tolerant to intrathecal morphine expressed increased CGRP and substance P‐like immunostaining in the dorsal horn of the spinal cord. The increase in CGRP, but not substance P‐like immunostaining, was blocked by a co‐treatment with CGRP8‐37 (4 μg). In animals already tolerant to morphine, the increase in CGRP but not substance P‐like immunostaining was partially reversed by CGRP8‐37 (4 μg). These data suggest that activation of spinal CGRP receptors contributes to both the development and expression of spinal opioid tolerance. CGRP receptor antagonists may represent a useful therapeutic approach for preventing as well as reversing opioid tolerance. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Blockade and reversal of spinal morphine tolerance by peptide and non‐peptide calcitonin gene‐related peptide receptor antagonists

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References (74)

Publisher
Wiley
Copyright
"Copyright © 2000 Wiley Subscription Services, Inc., A Wiley Company"
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0703655
pmid
11053206
Publisher site
See Article on Publisher Site

Abstract

This study examined the effects of the peptide CGRP receptor antagonist CGRP8‐37 and the newly‐developed non‐peptide CGRP receptor antagonist BIBN4096BS for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. Repeated administration of intrathecal morphine (15 μg), once daily, produced a progressive decline of antinociceptive effect and an increase in the ED50 value in the tailflick and paw pressure tests. Co‐administration of CGRP8‐37 (4 μg) or BIBN4096BS (0.05, 0.1 μg) with morphine (15 μg) prevented the decline of antinociceptive effect and increase in ED50 value in the tailflick test. Intrathecal administration of the CGRP receptor antagonists did not alter the baseline responses in either tests. Acute CGRP8‐37 also did not potentiate the acute actions of spinal morphine. In animals rendered tolerant to intrathecal morphine, subsequent administration of CGRP8‐37 (4 μg) with morphine (15 μg) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the reversal of tolerance. Animals tolerant to intrathecal morphine expressed increased CGRP and substance P‐like immunostaining in the dorsal horn of the spinal cord. The increase in CGRP, but not substance P‐like immunostaining, was blocked by a co‐treatment with CGRP8‐37 (4 μg). In animals already tolerant to morphine, the increase in CGRP but not substance P‐like immunostaining was partially reversed by CGRP8‐37 (4 μg). These data suggest that activation of spinal CGRP receptors contributes to both the development and expression of spinal opioid tolerance. CGRP receptor antagonists may represent a useful therapeutic approach for preventing as well as reversing opioid tolerance.

Journal

British Journal of Pharmacology – Wiley

Published: Nov 1, 2000

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