Abstract
Our study was designed to determine involvement of nitric oxide (NO) in the antinociception mediated by mu, delta andkappa opioid receptors in acute and prolonged pain in the rat spinal cord. The effect of intrathecally (i.t.) injected NO synthase inhibitors and opioid receptor agonists was evaluated in acute pain using a tail-flick and a paw pressure tests, and in prolonged pain by quantification the pain-related behavior after peripheral formalin injection. It was found that the neuronal NO synthase inhibitor 7-nitroindazole (50–400 μg), used in inactive doses, dose-dependently enhanced antinociception induced by morphine (0.5 μg) in the tail-flick and paw pressure. Moreover, coadministration of NG-nitro-l-arginine methyl ester (50 μg) another NO synthase inhibitor, with morphine (0.05–0.5 μg) as well as with specific agonists of mu([d-Ala2,N-Me-Phe4,Gly-ol5]enkephalin 0.1–2.5 ng) and delta([d-Pen2,5]enkephalin 0.02–0.5 μg) opioid receptors, enhanced dose-dependent antinociception in the tail-flick and paw pressure. Coadministration of NG-nitro-l-arginine methyl ester with specific kappa opioid receptor agonist 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzenacetamide (10–100 μg), produced antinociception in the paw pressure only. Additionally, NG-nitro-l-arginine methyl ester (100 μg) profoundly potentiated the antinociception induced by [d-Ala2,N-Me-Phe4,Gly-ol5]enkephalin (0.5, 15 ng) and [d-Pen2,5]enkephalin (2, 10 μg) in the dose-related manner in the formalin test. NG-nitro-l-arginine methyl ester (100 μg) also enhanced the antinociception induced by 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzenacetamide (10–100 μg) but only at the last two time points of the second phase of the formalin test. These data show that inhibition of the spinal NO synthase potentiates the mu-, delta- and to a lesser extent, kappa-mediated spinal antinociception in both acute and prolonged pain.
Footnotes
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Send reprint requests to: Dr. Barbara Przewłocka, Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Cracow, Poland.
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↵1 This work supported by a grant for statutory activity obtained from the Committee for Scientific Research (KBN, Warsaw).
- Abbreviations:
- cGMP
- cyclic guanosine monophosphate
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly-ol5]enkephalin
- DPDPE
- [d-Pen2,5]enkephalin
- EAA
- excitatory amino acid
- i.c.v.
- intracerebroventricular
- i.pl.
- intraplantar
- i.t.
- intrathecal
- L-NAME
- N-G-nitro-l-arginine methyl ester
- 7-NI
- 7-nitroindazole
- NO
- nitric oxide
- PP
- paw pressure
- TF
- tail-flick
- U50
- 488H, 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzenacetamide
- Received January 27, 1997.
- Accepted April 25, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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