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

1 This study examined the effects of the COX inhibitors, ketorolac and ibup rofen, and the NOS inhibitor L-NAME for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphin e. 2 Repeated administration of intrathecal morphine (15 mu g), once daily, re sulted in a progressive decline of antinociceptive effect and an increase i n the ED50 value in the tailflick and paw pressure tests. Co-administration of ketorolac (30 and 45 mu g) or S(+) ibuprofen (10 mu g) with morphine (1 5 mu g) prevented the decline of antinociceptive effect and increase in ED5 0 value. Similar treatment with L-NAME (100 mu g) exerted weaker effects. A dministration of S(+) but not R(-) ibuprofen (10 mg kg(-1)) had similar eff ects on systemic administration of morphine (15 mg kg(-1)). 3 Intrathecal or systemic administration of the COX or NOS inhibitors did n ot alter the baseline responses in either tests. Acute keterolac or S(+) ib uprofen also did not potentiate the acute actions of spinal or systemic mor phine, but chronic intrathecal administration of these agents increased the potency of acute morphine. 4 In animals already tolerant to intrathecal morphine, subsequent administr ation of ketorolac (30 mu g) with morphine (15 mu g) partially restored the antinociceptive effect and ED50 value of acute morphine, reflecting the re versal of tolerance. Intrathecal L-NAME (100 mu g) exerted a weaker effect. 5 These data suggest that spinal COX activity, and to a lesser extent NOS a ctivity, contributes to the development and expression of opioid tolerance. Inhibition of COX may represent a useful approach for the prevention as we ll as reversal of opioid tolerance.