Intravenous morphine increases the release of nitric oxide from spinal cord by an à-adrenergic and cholinergic mechanism. Zemin Xu, Chuanyao Tong, Hui-Lin Pan, Sergio E. Cerda, James C. Eisenach. Department of Anesthesia, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC, 27157-1009.
APStracts 4:0101N, 1997.
ABSTRACT
Systemic opioids produce analgesia in part by activating bulbospinal noradrenergic pathways. Spinally released norepinephrine (NE) has been suggested to produce analgesia in part by stimulating à2-adrenoceptors on cholinergic spinal interneurons to release acetylcholine (ACh). We hypothesized that this spinally released ACh would stimulate synthesis of nitric oxide (NO), and that spinally released NO following IV opioid injection would thus depend on a cascade of noradrenergic and cholinergic receptor stimulation. To test these hypotheses, IV morphine was administered to anesthetized sheep and neurotransmitters in dorsal horn interstitial fluid were measured by microdialysis. IV morphine increased NE and ACh in dorsal horn microdialysates, and these increases were inhibited by IV naloxone or cervical spinal cord transection. IV morphine also increased dorsal horn microdialysate concentrations of nitrite, a stable metabolite of NO. Increases in NE, ACh, and nitrite were antagonized by prior intrathecal injection of the à2-adrenergic antagonist, idazoxan, the muscarinic antagonist, atropine, or the NO synthase inhibitor, n-methyl-l-arginine (NMLA). To examine the concentration-dependent effects of spinal adrenergic stimulation, isolated rat spinal cord tissue was perfused with the à2- adrenergic agonist clonidine. Clonidine increased nitrite in the spinal cord tissue perfusate, an effect blocked by co-administration of idazoxan, atropine, and NMLA. These data support a previously hypothesized cascade of spinally released NE and ACh following systemic opioid administration. These data also suggest that spinally released NO plays a role in the analgesic effects of systemic opioids. In addition, these data imply a positive feedback whereby spinally released nitric oxide increases NE release and which has not previously been described. 

Received 3 January 1997; accepted in final form 16 June 1997.
APS Manuscript Number J2-7.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 15 July 1997