Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-arginine is considered to be a precursor substance of kyotorphin (tyrosyl-arginine), a [Met5]enkephalin releaser with antinociceptive action. We examined the antinociceptive effect of L-arginine in rats. L-Arginine (300-1000 mg/kg) administered subcutaneously (s.c.) elicited antinociception (assessed by the Randall-Selitto method) in rats with a carrageenin-treated hindpaw. Naloxone (2 mg/kg s.c.) but not N-methyl-levallorphan (20 mg/kg s.c.), a peripherally selective opioid antagonist, inhibited L-arginine-induced antinociception. Intracerebroventricular administration of L-arginine (0.2-1.0 mg/rat) produced a dose-related inhibition of the carrageenin-induced hyperalgesia. Intraplantar (i.pl.) injection of L-arginine (0.5-1.0 mg/paw) also induced antinociception, which was resistant to naloxone (2 mg/kg s.c.) but was antagonized by methylene blue (0.5 mg/paw i.pl.), a guanylate cyclase inhibitor. L-Arginine (1000 mg/kg s.c.) did not inhibit edema formation in the carrageenin-treated rat hindpaw. These results suggest that systemically administered L-arginine produces mainly an antinociceptive effect mediated by central opioidergic mechanisms in rats with carrageenin-induced hyperalgesia.
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PMID:Antinociceptive effect of L-arginine on the carrageenin-induced hyperalgesia of the rat: possible involvement of central opioidergic systems. 132 24

The association of [3H]-Met-enkephalin with synaptosomes isolated from rat brain cortex, when incubated for 30 min at 25 degrees C follows a sigmoid path with a Hill coefficient h = 1.25 +/- 0.04. Binding of Met-enkephalin into synaptosomes was saturable, with an apparent binding constant of 8.33 +/- 0.48 nM. At saturation, Met-enkephalin specific receptors corresponded to 65.5 +/- 7.2 nmol/mg synaptosomal protein. The Hill plot in combination with the biphasic nature of the curve to obtain the equilibrium constant, showed a moderate degree of positive cooperativity in the binding of Met-enkephalin into synaptosomes of at least one class of high affinity specific receptors. Met-enkephalin increased the lipid fluidity of synaptosomal membranes labelled with 1,6-diphenyl-1,3,5-hexatriene (DPH), as indicated by the steady-state fluorescence anisotropy [(ro/r)-1]-1. Arrhenius-type plots of [(ro/r)-1]-1 indicated that the lipid separation of the synaptosomal membranes at 23.4 +/- 1.2 degrees C was perturbed by Met-enkephalin such that the temperature was reduced to 15.8 +/- 0.8 degrees C. Naloxone reversed the fluidizing effect of Met-enkephalin, consistent with the receptor-mediated modulation of membrane fluidity. Naloxone alone had no effect on membrane fluidity. NO release and cGMP production by NO-synthase (NOS) and soluble guanylate cyclase (sGC), both located in the soluble fraction of synaptosomes (synaptosol) were decreased by 82% and 80% respectively, after treatment of synaptosomes with Met-enkephalin (10(-10)-10(-4) M). These effects were reversed by naloxone (10(-4) M) which alone was ineffective in changing NO and cGMP production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Met-enkephalin receptor-mediated increase of membrane fluidity modulates nitric oxide (NO) and cGMP production in rat brain synaptosomes. 754 Feb 62

Indomethacin, a typical cyclo-oxygenase inhibitor, acts as an analgesic by preventing the hyperalgesia induced by prostaglandins during inflammation. Analgesics of the dipyrone type directly block the sensitization of nociceptors. In the present investigation, the analgesic effect of diclofenac was compared with that of indomethacin in two algesimetric tests which permit discrimination between the two types of analgesic: the rat knee joint incapacitation and the rat paw hyperalgesia tests. The analgesics were given either pre- or posttreatment relative to the induction of hyperalgesia with carrageenin or prostaglandin E2. In both tests intraperitoneal pretreatment with indomethacin was equally or slightly more potent than diclofenac. Posttreatment with diclofenac was more effective than posttreatment with indomethacin. This was particularly evident in the paw hyperalgesia test in which posttreatment with indomethacin was not effective while diclofenac caused dose-dependent analgesia. When nociception was induced by PGE2 in both tests, the administration of indomethacin directly into the knee joint or rat paw had no effect while diclofenac continued to cause dose-dependent analgesia. Thus, diclofenac has a direct effect on ongoing hyperalgesia in addition to its ability to block cyclo-oxygenase. Naloxone and N-methyl-nalorphine did not affect diclofenac analgesia, thus indicating that the analgesic effect of the latter is independent of a central or peripheral opioid effect. Local administration of agents which inhibit the formation of nitric oxide (NG-monomethyl-L-arginine) or inhibit the activation of guanylate cyclase by nitric oxide (methylene blue) abolished diclofenac-induced analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of diclofenac analgesia: direct blockade of inflammatory sensitization. 790 38