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Comparative effects of cyclo‐oxygenase and nitric oxide synthase inhibition on the development and reversal of spinal opioid tolerance
Author(s) -
Powell Kelly J,
Hosokawa Akiko,
Bell Andrew,
Sutak Maaja,
Milne Brian,
Quirion Remi,
Jhamandas Khem
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702587
Subject(s) - morphine , ibuprofen , nociception , ketorolac , pharmacology , medicine , systemic administration , opioid , nitric oxide synthase , tail flick test , nitric oxide , anesthesia , drug tolerance , analgesic , receptor , in vivo , biology , microbiology and biotechnology
This study examined the effects 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. Repeated administration of intrathecal morphine (15 μg), once daily, resulted in a progressive decline of antinociceptive effect and an increase in the ED 50 value in the tailflick and paw pressure tests. Co‐administration of ketorolac (30 and 45 μg) or S(+) ibuprofen (10 μg) with morphine (15 μg) prevented the decline of antinociceptive effect and increase in ED 50 value. Similar treatment with L ‐NAME (100 μg) exerted weaker effects. Administration of S(+) but not R(−) ibuprofen (10 mg kg −1 ) had similar effects on systemic administration of morphine (15 mg kg −1 ). 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. In animals already tolerant to intrathecal morphine, subsequent administration of ketorolac (30 μg) with morphine (15 μg) partially restored the antinociceptive effect and ED 50 value of acute morphine, reflecting the reversal of tolerance. Intrathecal L ‐NAME (100 μg) exerted a weaker effect. 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.British Journal of Pharmacology (1999) 127 , 631–644; doi: 10.1038/sj.bjp.0702587