Spinal cord nitric oxide synthase and heme oxygenase limit morphine induced analgesia

• Published in: Brain research. Molecular brain research. Vol. 95; no. 1; pp. 96 - 102
• Main Authors: Li, Xiangqi, Clark, J.David
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.11.2001; Elsevier
• Subjects: Analgesics; Analgesics, Opioid - pharmacology; Animals; Biological and medical sciences; cGMP; Cyclic GMP - biosynthesis; Heme oxygenase; Heme Oxygenase (Decyclizing) - metabolism; Hyperalgesia; In Vitro Techniques; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Morphine - pharmacology; Neuropharmacology; Nitric oxide synthase; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type I; Null-mutant; Pain Measurement; Pharmacology. Drug treatments; Spinal Cord - enzymology; Spinal Cord - metabolism; Heme oxygenase; Sensory systems; Nitric oxide synthase; cGMP; Morphine; Null-mutant; Hyperalgesia; Spinal cord; Enzyme; Rodentia; Central nervous system; Heme oxygenase (decyclizing); 3',5'-GMP; Opiates; Narcotic analgesic; Nitric-oxide synthase; Analgesia; Vertebrata; Mammalia; Mouse; Animal; Oxidoreductases
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/S0169-328X(01)00251-0

Spinal cord tissue contains two enzyme systems capable of producing monoxide gasses which in turn are linked to the stimulation of soluble guanylate cyclase, nitric oxide synthase (NOS) which produces NO and heme oxygenase (HO) which produces CO. Reports from several laboratories link these two enzyme systems to pain of inflammatory and neuropathic etiologies. Additional studies have demonstrated that the activation of the NOS system by morphine limits the spinal analgesic action of this drug. In this study we first employed the hot plate model of pain to demonstrate that the NOS inhibitor l-NAME and the HO inhibitor Sn-P potentiate the analgesic actions of intrathecally administered morphine while having no intrinsic analgesic action at the doses used. We then determined that l-NAME loses its ability to potentiate morphine in nNOS null-mutant mice, while Sn-P no longer potentiates morphine in mice lacking a functional HO-2 gene. The intrathecal injection of the cGMP analog 8-Br cGMP caused hyperalgesia in the hot plate assay. Focusing on the possible involvement of cGMP metabolism, we documented that morphine stimulates cGMP production in a spinal cord slice model in a concentration dependent and naloxone reversible manner. Both l-NAME and Sn-P were potent inhibitors of morphine-stimulated cGMP production. Buffer containing either CO or the NO donor compound SNAP stimulated cGMP production as well. In spinal cord slices from either nNOS or HO-2 null-mutant animals morphine did not stimulate cGMP production. Taken together our data suggest that spinal monoxide generation modifies the acute analgesic actions of morphine.