ABSTRACT
The present study was undertaken to investigate the role of inducible nitric oxide synthase in a rat model of persistent pain. The effects of L-N6 (1-iminoethyl) lysine (L-NIL), a relatively potent and relatively selective inhibitor of inducible nitric oxide synthase, were investigated in carrageenan induced hyperalgesia L-NIL (0.1 microMole) injected intraplantar or intrathecal markedly enhanced carrageenan induced hyperalgesia. These effects were reversed during the third hour by co-administration of L-arginine (900 mg/kg i.p.) but not D-arginine. Methylene blue (MB), a soluble guanylate cyclase inhibitor, administered intrathecally (0.1 microg) had no effect on L-NIL potentiation of carrageenan hyperalgesia but abolished antinociception induced by L-arginine. Obtained results suggest that nitric oxide derived from inducible nitric oxide synthase play an inhibitory role in carrageenan produced hyperalgesia in rat.
Subject(s)
Enzyme Inhibitors/pharmacology , Lysine/analogs & derivatives , Nitric Oxide Synthase/antagonists & inhibitors , Pain/etiology , Animals , Arginine/pharmacology , Carrageenan/pharmacology , Chronic Disease , Lysine/pharmacology , Male , Methylene Blue/pharmacology , Nitric Oxide Synthase Type II , Pain/enzymology , Rats , Rats, WistarABSTRACT
Intrathecal injection of 0.25 micrograms of undecapeptide substance P antagonist (SPA) produced transient antinociception with a peak effect at 5 min. Increasing the SPA dose resulted in neurotoxicity. Intrathecal injection of the opioid peptide biphalin (BIP) produced antinociception for over 3 hrs without neurotoxicity. Co-administration of SPA (at subtoxic doses) increased BIP's antinociceptive effect. Naltrexone reversed analgesia due to BIP alone as well as after BIP+SPA.
Subject(s)
Analgesics/administration & dosage , Enkephalins/administration & dosage , Pain/drug therapy , Substance P/analogs & derivatives , Analgesics/pharmacology , Animals , Drug Synergism , Enkephalins/pharmacology , Injections, Spinal , Male , Naltrexone/pharmacology , Pain Measurement , Rats , Rats, Wistar , Substance P/administration & dosage , Substance P/antagonists & inhibitors , Substance P/pharmacologyABSTRACT
Synthesis of four new N,N-disubstituted derivatives of enkephalin analogs: All2Tyr-DMet-Gly-Phe-epsilon Ahx-OMe 5, Bu2Tyr-DMet-Gly-Phe-epsilon Ahx-OMe 6, All2Tyr-DMet-Gly-Phe-epsilon Ahx-epsilon Ahx-OMe 11 and Bu2Tyr-DMet-Gly-Phe-epsilon Ahx-epsilon Ahx-OMe 12 is reported. they were tested for agonistic and antagonistic activity. Compound 5 is a little more potent agonist (IC50 = 1.9 x 10(-7) M/l, GPI) than compound 6(IC50 = 7.2 x 10(-7) M/l, GPI). They both are highly selective to mu receptor, because they show no trace of activity to delta receptor in concentration up to 10(-5) M/l. Compound 11 and 12 are less active and not selective as agonists. None of these compounds showed antagonistic activity.
Subject(s)
Enkephalins/chemical synthesis , Amino Acid Sequence , Animals , Chromatography, High Pressure Liquid , Enkephalins/pharmacology , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Magnetic Resonance Spectroscopy , Male , Mice , Molecular Sequence Data , Morphine/pharmacology , Muscle, Smooth/drug effects , Vas Deferens/drug effectsABSTRACT
Synthesis of four new derivatives of enkephalin analogs: H-BuTyr-DMet-Gly- Phe-epsilon Ahx-OH 9, H-BzlTyr-DMet-Gly-Phe-epsilon Ahx-OH 12, H-Butyr-DMet-Gly- -Phe-epsilon Ahx-epsilon Ahx-OH 15 and H-BzlTyr-DMet-Gly-Phe-epsilon Ahx-OH is reported. They were examined for agonistic, antagonistic and analgesic activity. Compound 12 is the most potent among investigated peptides. Its agonistic activity in vitro is 7.85 x 10(-8) M/l (GPI) and 9.5 x 10(-7) M/l (MVD). None of the peptides showed antagonistic activity. Only compound 12 showed weak, not dose-dependent analgesic activity in rats.
Subject(s)
Enkephalins/chemical synthesis , Amino Acid Sequence , Amino Acids/analysis , Animals , Chromatography, High Pressure Liquid , Enkephalins/chemistry , Guinea Pigs , In Vitro Techniques , Magnetic Resonance Spectroscopy , Male , Mice , Molecular Sequence Data , Morphine/antagonists & inhibitors , Morphine/pharmacology , Naloxone/pharmacology , Rats , Rats, Inbred Strains , Receptors, Opioid/drug effects , Receptors, Opioid/metabolismSubject(s)
Arrhythmias, Cardiac/drug therapy , Flecainide/therapeutic use , Arrhythmias, Cardiac/physiopathology , Drug Evaluation , Flecainide/pharmacokinetics , Flecainide/toxicity , Heart Conduction System/drug effects , Heart Conduction System/physiopathology , Hemodynamics/drug effects , HumansABSTRACT
Pirolo [3,4-e] [1,4]-diazepine derivatives: 5-(2'-naphtyl) (7-phenyl-) 2, 3, 6, 8-tetrahydro)-pirolo-[3,4-e] [1,4]-diazepine-6-thiox-8-(1H,7H)-one (PD) and 5-(2'-naphtyl) 7-p-chlorophenyl-(2, 3, 6, 8-tetrahydro)-pirolo-[3,4-e] [1,4]-diazepine-6-thiox-8-(1H, 7H)-one (PDC1) show distinct analgesic properties, but no marked antiinflammatory activity in vivo. In addition these compounds inhibit rat blood platelet aggregation in vivo, and produce contractions of the rat's pregnant uterus.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Azepines/chemical synthesis , Animals , Aspirin/pharmacology , Azepines/pharmacology , Carrageenan , Chemical Phenomena , Chemistry , Edema/chemically induced , Female , Gossypium , Granuloma/chemically induced , In Vitro Techniques , Indomethacin/pharmacology , Male , Mice , Platelet Aggregation/drug effects , Pleurisy/chemically induced , Pregnancy , Rats , Rats, Inbred Strains , Reaction Time/drug effects , Turpentine , Uterine Contraction/drug effectsABSTRACT
The effects of double endorphins DALA2, DYNO2, CASO2 on pain threshold in the rats were compared with those of DALA (D-Ala2-Met5-enkephalinamide). Marked differences in the analgesic potency of the investigated peptides were noted. The most potent analgesic effect was exerted by DALA2. DYNO2 was weaker than DALA and DALA2 due to lack of glycine residue in position 3, probably responsible for the receptor affinity and analgesic activity in vivo. The weak analgesic activity of CASO2 in vivo corresponds with the weak opiate agonistic action of this peptide in vitro [see 7]. All investigated peptides induced changes in animal behaviour when injected i.c.v. The results indicated that among peptides in the novel group of double endorphins, DALA2 is of special interest because of a potent and long lasting analgesic action.
Subject(s)
Analgesia , Enkephalin, Methionine/analogs & derivatives , Enkephalins/pharmacology , Oligopeptides , Animals , Behavior, Animal/drug effects , Enkephalin, Methionine/pharmacology , Male , Rats , Rats, Inbred Strains , Time FactorsABSTRACT
Effects of substance P (SP) administered into anterior hypothalamus or lateral ventricle on body temperature were investigated. When administered into lateral ventricle in doses from 20 to 2000 ng SP failed to influence body temperature. Application of SP into anterior hypothalamus in the same doses (20-2000 ng) resulted in a mild but insignificant increase in body temperature. No visible changes in the behavior of the rats, except slight sedation after the highest dose administered into lateral ventricle, were observed after application of SP. These results suggest that SP does not play any essential role in thermoregulation.
