SPINAL NMDA RECEPTOR - NITRIC-OXIDE MEDIATION OF THE EXPRESSION OF MORPHINE-WITHDRAWAL SYMPTOMS IN THE RAT

Previous studies in this laboratory have demonstrated that cholinergic receptors within the spinal cord play an important role in the expression of naloxone-precipitated withdrawal symptoms in the morphine-dependent rat. Related cardiovascular studies in non-dependent animals have demonstrated that this spinal cholinergic system is linked to a glutamatergic, NMDA presser pathway which also involves the participation of a nitric oxide (NO) generating system. The purpose of this study was to determine whether spinal NMDA receptors and/or NO are involved in the expression of morphine withdrawal symptoms. Rats bearing previously implanted intrathecal (IT) catheters were dependent on morphine following chronic i.a. infusion of increasing doses over 5 days. Naloxone (0.5 mg/kg) was administered via the i.a. line to precipitate withdrawal; and both cardiovascular and behavioral symptoms were recorded over 60 min. Pretreatment 20 min before naloxone with IT injection of either of the NMDA receptor antagonists, MK-801 or AP-7 (100-200 nmol), produced a significant reduction in the expression of both the cardiovascular and behavioral symptoms of up to about 60%. IT pretreatment with the NO synthase inhibitor L-NAME - a methyl ester derivative of L-arginine, also produced a dose-dependent, L-arginine reversible inhibition of the cardiovascular (mainly the presser) component of withdrawal, but had no significant effect on the expression of behavioral signs. In contrast, IT pretreatment with L-NOARG and L-NMMA, non-ester analogs of L-arginine, significantly inhibited the expression of the behavioral signs of withdrawal but did not alter the presser component. A combined pretreatment with L-NAME and L-NOARG resulted in suppression of both presser and behavioral components of withdrawal. The anti-withdrawal actions of either class of NO synthase inhibitor could not be attributed to blockade of local muscarinic receptors. These findings are consistent with a role for both spinal NMDA receptors and a NO generating system in the expression of both the behavioral and autonomic components of naloxone-precipitated withdrawal. They also suggest that different structural analogs of L-arginine have different profiles of activity in this regard - opening the possibility that different isozymes of NO synthase located within the same spinal region mediate different physiological or behavioral functions.