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Inhibition of neuronal nitric oxide synthase attenuates the development of morphine tolerance in rats
Author(s) -
Santamarta María Teresa,
Ulibarri Isabel,
Pineda Joseba
Publication year - 2005
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20151
Subject(s) - locus coeruleus , morphine , nociception , opioid , pharmacology , nitric oxide synthase , nitric oxide , chemistry , agonist , receptor , tail flick test , medicine , endocrinology , central nervous system , biochemistry
Our previous results have shown the involvement of nitric oxide in acute opioid desensitization of μ‐opioid receptors in vitro. In the present study, we investigated the effect of repeated administration of 7‐nitroindazole (7‐NI; 30 mg/kg/12 h, i.p., 3 days), an inhibitor of neuronal nitric oxide synthase in vivo, on μ‐opioid receptor tolerance induced by subchronic treatment with morphine in rats. The inhibitory effect of the opioid agonist Met 5 ‐enkephalin (ME) on the cell firing rate was evaluated by single‐unit extracellular recordings of noradrenergic neurons in the locus coeruleus from brain slices, and the antinociceptive effect of morphine was measured by tail‐flick techniques. In morphine‐treated animals, concentration‐effect curves for ME in the locus coeruleus were shifted by 5‐fold to the right as compared to those in sham‐treated animals, which confirmed the induction of μ‐opioid receptor tolerance. However, tolerance to ME in morphine‐treated rats was fully prevented by co‐administration of 7‐NI when compared to the vehicle‐morphine group. Likewise, the antinociceptive effect of morphine was reduced in morphine‐treated animals as compared to the sham group, whereas the antinociceptive tolerance was partially prevented by co‐administration of 7‐NI in morphine‐treated rats (when compared to the vehicle‐morphine group). Finally, 7‐NI administration in sham‐treated rats failed to change the effect induced by ME on the locus coeruleus or by morphine in the tail‐flick test as compared to vehicle groups. These results demonstrate that subchronic administration of a neuronal inhibitor of nitric oxide synthase attenuates the development of morphine tolerance to the cellular and analgesic effects of μ‐opioid receptor agonists. Synapse 57:38–46, 2005. © 2005 Wiley‐Liss, Inc.