naltrindole and kyotorphin

We investigated the role of spinal opioid receptors in the antinociceptive effect of kyotorphin (Tyr-Arg, KTP) by using an in vivo mice tail-pinch test and an in vitro opioid receptor binding assays. Intrathecal administration of KTP produced a dose-dependent antinociceptive effect with an ED(50) value of 24 microg/mouse. This antinociception, which was reversed by the KTP antagonist Leu-Arg, was completely blocked by naltrindole but not by naloxonazine, beta-funaltrexamine, or nor-binaltorphimine. The results from the binding study in vitro indicated that KTP bound to spinal KTP receptors but not to any opioid receptors in the mouse spinal cord. These results suggest that KTP-induced antinociception is mediated by binding to KTP receptors followed by an indirect activation of the delta-opioid receptors in the spinal cord.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Endorphins; Injections, Spinal; Male; Mice; Naltrexone; Narcotic Antagonists; Pain Measurement; Receptors, Opioid, delta; Spinal Cord

Topics: Adaptation, Physiological; Animals; Arrhythmias, Cardiac; Calcium Chloride; Disulfides; Endorphins; Enzyme Inhibitors; Epinephrine; Male; Naltrexone; Narcotic Antagonists; Neprilysin; Phenylalanine; Rats; Rats, Wistar; Receptors, Opioid

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

1. Intracerebroventricular (i.c.v.) administration of L-arginine (L-Arg), at 10-100 micrograms per mouse, produced antinociception in mice, as assessed by the tail flick test; this antinociception was reversed by pretreatment (s.c.) with naltrindole (NTI), a delta-selective opioid antagonist, and by co-administered L-leucyl-L-arginine (Leu-Arg), a kyotorphin (endogenous Met-enkephalin releaser) receptor antagonist. 2. L-NG-nitroarginine methyl ester (L-NAME), a NO synthase inhibitor, but not D-NG-nitroarginine methyl ester, given i.c.v. at 3-10 micrograms per mouse, exhibited antinociceptive activity that was resistant to naloxone (s.c.), NTI (s.c.) and Leu-Arg (i.c.v.). 3. The L-NAME (i.c.v.)-induced antinociception was not reversed by L-Arg (i.c.v.), which was antinociceptive by itself, but was abolished by combined injection of L-Arg plus Leu-Arg (i.c.v.) or by L-Arg (i.c.v.) after NTI (s.c.). 4. Methylene blue (MB), a soluble guanylate cyclase inhibitor, at 0.1-1 microgram per mouse, produced antinociception by i.c.v. administration. The antinociception induced by MB (i.c.v.) or L-NAME (i.c.v.) was reversed by co-administered dibutyryl cyclic GMP. 5. These findings suggest that L-Arg plays a dual role in nociceptive processing in the brain, being antinociceptive via the kyotorphin-Met-enkephalin pathway and nociceptive via the NO-cyclic GMP pathway.

Topics: Analgesics; Animals; Arginine; Brain; Cyclic GMP; Endorphins; Enkephalin, Methionine; Injections, Intraventricular; Male; Methylene Blue; Mice; Mice, Inbred Strains; Naloxone; Naltrexone; Narcotic Antagonists; Neural Pathways; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nociceptors; Pain Measurement; Spinal Cord

1. Intraplantar injection of carrageenin into the mouse hind paw produced hyperalgesia when measured by the paw pressure test (Randall & Selitto method). 2. Subcutaneous administration of L-arginine (100-1,000 mg kg-1), a possible precursor of kyotorphin which is an endogenous analgesic neuropeptide, inhibited carrageenin-induced hyperalgesia in a dose-dependent manner. This effect was blocked by subcutaneous administration of naloxone, naltrindole, a selective delta-opioid receptor antagonist (enkephalin antagonist), and D-arginine. 3. Intracerebroventricular administration of L-leucyl-L-arginine inhibited the antinociceptive effect of systemically administered L-arginine in hyperalgesic mice. 4. Intracerebroventricular administration of L-arginine (3 and 30 micrograms per mouse) and kyotorphin (300 ng-3 micrograms per mouse) produced antinociception in hyperalgesic mice. The antinociceptive effects of L-arginine but not kyotorphin were blocked by intracerebroventricular administration of D-arginine. 5. These results suggest that L-arginine-induced antinociception is mediated by activation of 'kyotorphinergic' nerves followed by activation of the 'opioidergic' (possible 'enkephalinergic') nerves in the central nervous system.

Topics: Analgesics; Animals; Arginine; Brain; Carrageenan; Dipeptides; Endorphins; Hyperalgesia; Indoles; Injections, Subcutaneous; Male; Mice; Morphinans; Naltrexone; Narcotic Antagonists; Pain Measurement; Stereoisomerism