nitroarginine and kyotorphin

L-Tyrosyl-L-arginine (kyotorphin) is known as an endogenous analgesic neuropeptide. We examined whether kyotorphin and other arginine-containing neuropeptides were endogenous substrates for neuronal nitric oxide synthase (NOS) in the rat brain. Cytosol fractions of the rat cerebellum contained higher concentrations of neuronal NOS (nNOS) than endothelial NOS. In rat cerebellar cytosol, the binding activity of [3H]NG-nitro-L-arginine (NNA) was inhibited equally by L-arginine (L-Arg), kyotorphin, and L-leucyl-L-Arg (a kyotorphin receptor antagonist). Binding activities were inhibited to lesser degrees by fibronectin active fragments, bradykinin, and dynorphin A, but were not inhibited by L-tyrosyl-D-Arg or substance P. Interestingly, the inhibition of [3H]NNA binding by kyotorphin was attenuated by inhibitors of kyotorphin-hydrolyzing peptidases (KTPases) such as bestatin and arphamenine B. These results suggest that kyotorphin is degraded to L-Arg by KTPases, which in turn may act as substrate for nNOS.

Topics: Animals; Arginine; Bradykinin; Brain; Cerebellum; Cerebral Cortex; Cytosol; Dipeptides; Dynorphins; Endorphins; Fibronectins; Hippocampus; Immunoblotting; Neurons; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Tritium

The antinociceptive effect of L-arginine in streptozotocin-induced diabetic mice was examined. Although s.c. administration of L-arginine produced a dose-dependent inhibition of the tail-flick response in both non-diabetic and diabetic mice, the antinociceptive response was greater in diabetic mice than in non-diabetic mice. The antinociceptive effects of L-arginine in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of naltrindole, a selective delta-opioid receptor antagonist. However, neither beta-funaltrexamine, a selective mu-opioid receptor antagonist, nor nor-binaltorphimin ++, a selective kappa-opioid receptor antagonist, significantly affected the antinociceptive effect of L-arginine in diabetic and non-diabetic mice. These results suggest that L-arginine produces a marked antinociceptive effect in diabetic mice through the activation of delta-opioid receptors.

Topics: Analgesics; Animals; Arginine; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Endorphins; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Nitroarginine; Pain Measurement; Reaction Time