INTRAVENOUS MORPHINE INCREASES RELEASE OF NITRIC-OXIDE FROM SPINAL-CORD BY AN ALPHA-ADRENERGIC AND CHOLINERGIC MECHANISM

Systemic opioids produce analgesia in part by activating bulbospinal n oradrenergic pathways. Spinally released norepinephrine (NE) has been suggested to produce analgesia in part by stimulating alpha(2)-adrenoc eptors on cholinergic spinal interneurons to release acetylcholine (AC h). We hypothesized that this spinally released ACh would stimulate sy nthesis of nitric oxide (NO), and that spinally released NO after intr avenous (IV) opioid injection thus would depend on a cascade of noradr energic and cholinergic receptor stimulation. To test these hypotheses , IV morphine was administered to anesthetized sheep, and neurotransmi tters 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 TV naloxone or cervical spinal cord transection. IV morphine also increased dorsal horn microdialysate co ncentrations of nitrite, a stable metabolite of NO. Increases in NE, A Ch, and nitrite were antagonized by prior intrathecal injection of the alpha(2)-adrenergic antagonist idazoxan, the muscarinic antagonist at ropine, or the NO synthase inhibitor N-methyl-L-arginine (NMLA). To ex amine the concentration-dependent effects of spinal adrenergic stimula tion, isolated rat spinal cord tissue was perfused with the alpha(2)-a drenergic agonist clonidine. Clonidine increased nitrite in the spinal cord tissue perfusate, an effect blocked by coadministration of idazo xan, atropine, and NMLA. These data support a previously hypothesized cascade of spinally released NE and ACh after systemic opioid administ ration. 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 incr eases NE release and that has not previously been described.