Inhibition of neuronal nitric oxide synthase attenuates the development of morphine tolerance in rats

Synapse - Tập 57 Số 1 - Trang 38-46 - 2005
María Teresa Santamarta1, Isabel Ulibarri1, Joseba Pineda2
1Department of Pharmacology, Faculty of Medicine, University of the Basque Country, E-48940 Leioa, Bizkaia, Spain
2Farmakologia Saila, Medikuntza Fakultatea, Euskal Herriko Unibertsitatea (UPV/EHU), E‐48940 Leioa, Bizkaia, Spain

Tóm tắt

AbstractOur 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 Met5‐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.

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Synapse

Tập 57 Số 1

38-46

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