HYDROGEN-CYANIDE GENERATION BY MU-OPIATE RECEPTOR ACTIVATION - POSSIBLE NEUROMODULATORY ROLE OF ENDOGENOUS CYANIDE

Hydrogen cyanide, a gaseous molecule, is produced by white blood cells during phagocytosis. The present study examined the possibility that neuronal-like cells may also produce cyanide following activation. Rat pheochromocytoma (PC12) cells exhibited a low level of cyanide genera tion that was significantly increased by CL-opiate agonists (hydromorp hone, morphine) and blocked by naloxone. A variety of other agonists i ncluding bradykinin, nicotine and glutamate did not generate cyanide i n PC12 cells. Systemic administration of hydromorphone to rats increas ed brain cyanide levels by 61% after 15 min. Using microdialysis probe s implanted in the cortical-hippocampal areas of the anesthetized rat or in the hypothalamus of the conscious hamster, a 2- to 9-fold increa se in cyanide generation was seen after hydromorphone administration a nd this increase was blocked by naloxone. To determine whether cyanide release by hydromorphone has functional significance in a neuronal sy stem, cyanide enhancement of N-methyl-D-aspartate (NMDA)-induced incre ased [Ca2+](i) was measured in rat cerebellar granule cells. Hydromorp hone enhanced the response to NMDA similar to cyanide and the hydromor phone effect was blocked by cyanide scavengers. These data show that c yanide generation is increased in neuronal tissue by a mu-opiate recep tor agonist and it is proposed that endogenous cyanide may modulate th e NMDA receptor response. (C) 1997 Elsevier Science B.V.