Comparative effects of cyclo‐oxygenase and nitric oxide synthase inhibition on the development and reversal of spinal opioid tolerance

Abstract

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.

Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats

“…The role of these mediators in the development of morphine tolerance and opioid withdrawal-induced hyperalgesia is well documented (Mao et al, 1995;Powell et al, 1999;Raghavendra et al, 2002). In the present study, we observed that the propentofylline attenuation of morphine tolerance and its withdrawal-induced hyperalgesia was also associated with decreased spinal proinflammatory immune responses.…”

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

“…As was observed in our previous studies (Mendard et al, 1996), CGRP 8-37 inhibited the development of morphine tolerance, and this eect was mimicked by BIBN4096BS. The action of CGRP receptor blockade on the development of tolerance to spinal morphine was not due to a potentiation of acute morphine action, or a sensitization to morphine as was previously observed with the NMDA receptor antagonist MK801 (Dunbar & Yaksh, 1996) or inhibitors of cyclooxygenase activity like ketorolac and ibuprofen (Powell et al, 1999). In fact, BIBN4096BS slightly inhibited the acute antinociceptive action of morphine in the tail-¯ick test but still attenuated the loss of morphine potency associated with chronic treatment.…”

“…Thus, an increase in substance P activity could reduce the ability of opioids to inhibit transmitter release and produce antinociception. We have recently shown that intrathecal application of prostanoid synthesis inhibitors eectively blocks and reverses the development of opioid tolerance (Powell et al, 1999). Our preliminary ®ndings with a substance P receptor antagonist (SR140333) have also revealed its potential to inhibit spinal morphine tolerance (Powell et al, 1999, unpublished results).…”

“…Previous experiments have shown that established tolerance can be reversed by pharmacological manipulation of NMDA receptor activity with antagonists such as ketamine and LY274614 (Tiseo & Inturrisi, 1993;Elliott et al, 1994;Shimoyama et al, 1996). Additionally, the inhibition of the production of intermediaries of NMDA receptor activity (prostaglandins and nitric oxide) also reverses established tolerance (Kolesnikov et al, 1993;Powell et al, 1999). Since CGRP can release Lglutamate (Kangrga et al, 1990) and enhance NMDA receptor-mediated excitation (Murase et al, 1989), it is likely that CGRP also contributes to the maintenance of tolerance.…”

COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia

“…Tolerance to the analgesic effect of opioids is believed to be mediated at least partly by prostaglandin-mediated mechanisms (Powell et al, 1999). Intrathecal administration of COX-2 inhibitors attenuates the development of tolerance to morphine (Wong et al, 2000).…”