ENDOGENOUS NITRIC-OXIDE IS REQUIRED FOR TONIC CHOLINERGIC INHIBITION OF SPINAL MECHANICAL TRANSMISSION

Recent studies have suggested that a spinal cholinergic system is impo rtant in spinal nociceptive modulation. In the present study, the role of a nitric oxide (NO)-generating system in spinal cholinergic modula tion of nociception was examined in awake rats. Intrathecal (i.t.) adm inistration of the cholinergic muscarinic receptor antagonist atropine produced a dose-dependent (1.4-14.4 nmol) decrease in the mechanical threshold for tail withdrawal, which was reversed rapidly (2-3 min) by subsequent i.t. administration of the NO precursor, L-arginine (10 pm ol to 10 nmol). Intrathecal administration Of L-arginine alone (10 pmo l to 10 nmol) produced a dose-dependent increase in the mechanical noc iceptive withdrawal threshold of the tail. The reflexive withdrawal of the tail produced by noxious heat was not significantly affected by i .t. administration of either atropine or L-arginine. Inhibition of the NO-cGMP pathway by i.t. administration of either N(w)-nitro-L-arginin e methyl ester (L-NAME, 10 nmol) or methylene blue (10 nmol) significa ntly enhanced the magnitude and prolonged the time course of the decre ase in the mechanical threshold for tail withdrawal produced by i.t. p retreatment with atropine (1.4 nmol). Neither L-NAME nor methylene blu e affected mechanical withdrawal thresholds in rats pretreated with sa line. These data suggest that the production of endogenous NO is requi red for tonic inhibition of spinal nociceptive mechanical transmission . Moreover, the present data support the speculation that there exists in the lumbar spinal cord a tonic, cholinergic modulation of NO synth ase.