1 This study examined the eects of the peptide CGRP receptor antagonist CGRP 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. 2 Repeated administration of intrathecal morphine (15 mg), once daily, produced a progressive decline of antinociceptive eect and an increase in the ED 50 value in the tail¯ick and paw pressure tests. Co-administration of CGRP 8-37 (4 mg) or BIBN4096BS (0.05, 0.1 mg) with morphine (15 mg) prevented the decline of antinociceptive eect and increase in ED 50 value in the tail¯ick test. Intrathecal administration of the CGRP receptor antagonists did not alter the baseline responses in either tests. Acute CGRP 8-37 also did not potentiate the acute actions of spinal morphine. 3 In animals rendered tolerant to intrathecal morphine, subsequent administration of CGRP (4 mg) with morphine (15 mg) partially restored the antinociceptive eect and ED 50 value of acute morphine, re¯ecting the reversal of tolerance. 4 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 Plike immunostaining, was blocked by a co-treatment with CGRP 8-37 (4 mg). In animals already tolerant to morphine, the increase in CGRP but not substance P-like immunostaining was partially reversed by CGRP 8-37 (4 mg). 5 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.

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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1 This study examined the eects of the COX inhibitors, ketorolac and ibuprofen, and the NOS inhibitor L-NAME for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. 2 Repeated administration of intrathecal morphine (15 mg), once daily, resulted in a progressive decline of antinociceptive eect and an increase in the ED 50 value in the tail¯ick and paw pressure tests. Co-administration of ketorolac (30 and 45 mg) or S(+) ibuprofen (10 mg) with morphine (15 mg) prevented the decline of antinociceptive eect and increase in ED 50 value. Similar treatment with L-NAME (100 mg) exerted weaker eects. Administration of S(+) but not R(7) ibuprofen (10 mg kg 71) had similar eects on systemic administration of morphine (15 mg kg 71 ). 3 Intrathecal or systemic administration of the COX or NOS inhibitors did not alter the baseline responses in either tests. Acute keterolac or S(+) ibuprofen also did not potentiate the acute actions of spinal or systemic morphine, but chronic intrathecal administration of these agents increased the potency of acute morphine. 4 In animals already tolerant to intrathecal morphine, subsequent administration of ketorolac (30 mg) with morphine (15 mg) partially restored the antinociceptive eect and ED 50 value of acute morphine, re¯ecting the reversal of tolerance. Intrathecal L-NAME (100 mg) exerted a weaker eect. 5 These data suggest that spinal COX activity, and to a lesser extent NOS activity, contributes to the development and expression of opioid tolerance. Inhibition of COX may represent a useful approach for the prevention as well as reversal of opioid tolerance.