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

1 This study examined the effects of the peptide CGRP receptor antagonist C GRP(8-37) and the newly-developed non-peptide CGRP receptor antagonistBIBN4 096BS for their potential to both inhibit the development and reverse toler ance to the antinociceptive action of morphine. 2 Repeated administration of intrathecal morphine (15 mug), once daily, pro duced a progressive decline of antinociceptive effect and an increase in th e ED50 value in the tailflick and paw pressure tests. Go-administration of CGRP(8-37) (4 mug) or BIBN4096BS (0.05, 0.1 mug) with morphine (15 mug) pre vented the decline of antinociceptive effect and increase in ED50 value in the tailflick test. Intrathecal administration of the CGRP receptor antagon ists did not alter the baseline responses in either tests. Acute CGRPs(8-37 ) also did not potentiate the acute actions of spinal morphine. 3 In animals rendered tolerant to intrathecal morphine, subsequent administ ration of CGRP(8-37) (4 mug) with morphine (15 mug) partially restored the antinociceptive effect and EDS, value of acute morphine, reflecting the rev ersal of tolerance. 4 Animals tolerant to intrathecal morphine expressed increased CGRP and sub stance P-like immunostaining in the dorsal horn of the spinal cord. The inc rease in CGRP, but not substance P-like immunostaining, was blocked by a co -treatment with CGRP(8.37) (4 mug). In animals already tolerant to morphine , the increase in CGRP but not substance P-like immunostaining was partiall y reversed by CGRP(8-37) (4 mug). 5 These data suggest that activation of spinal CGRP receptors contributes t o both the development and expression of spinal opioid tolerance. CGRP rece ptor antagonists may represent a useful therapeutic approach for preventing as well as reversing opioid tolerance.