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J Neurophysiol 78: 2072-2078, 1997;
0022-3077/97 $5.00
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The Journal of Neurophysiology Vol. 78 No. 4 October 1997, pp. 2072-2078
Copyright ©1997 The American Physiological Society

Intravenous Morphine Increases Release of Nitric Oxide From Spinal Cord by an alpha -Adrenergic and Cholinergic Mechanism

Zemin Xu, Chuanyao Tong, Hui-Lin Pan, Sergio E. Cerda, and James C. Eisenach

Department of Anesthesia, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157-1009

Xu, Zemin, Chuanyao Tong, Hui-Lin Pan, Sergio E. Cerda, and James C. Eisenach. Intravenous morphine increases release of nitric oxide from spinal cord by an alpha -adrenergic and cholinergic mechanism. J. Neurophysiol. 78: 2072-2078, 1997. 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 alpha 2-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 after intravenous (IV) opioid injection thus would 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 alpha 2-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 alpha 2-adrenergic agonist clonidine. Clonidine increased nitrite in the spinal cord tissue perfusate, an effect blocked by coadministration of idazoxan, atropine, and NMLA. These data support a previously hypothesized cascade of spinally released NE and ACh after 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 that has not previously been described.




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