naltrindole and ubenimex

The aim of this study was to investigate this involvement in not inflammatory model of pain and which opioid receptor subtype mediates noradrenaline-induced peripheral antinociception. Noradrenaline is involved in the intrinsic control of pain-inducing pro-nociceptive effects in the primary afferent nociceptors. However, inflammation can induce various plastic changes in the central and peripheral noradrenergic system that, upon interaction with the immune system, may contribute, in part, to peripheral antinociception.. Hyperalgesia was induced by intraplantar injection of prostaglandin E. Intraplantar injection of NA induced peripheral antinociception against hyperalgesia induced by PGE. Besides the α

Topics: Analgesics; Animals; Cinnamates; Dinoprostone; Dose-Response Relationship, Drug; Hyperalgesia; Leucine; Male; Morphine Derivatives; Naltrexone; Norepinephrine; Opioid Peptides; Pain Measurement; Prazosin; Propranolol; Rats; Yohimbine

Intrathecal (i.t.) injection of leucine-enkephalin (Leu-ENK), co-administered with peptidase inhibitors, phosphoramidon (an endopeptidase 24.11 inhibitor), and bestatin (a general aminopeptidase inhibitor), produced behaviors consisting of the biting and/or licking of the hindpaw and the tail along with hindlimb scratching directed toward the flank, which peaked at 10-15 min after an injection. This characteristic behavior was not observed in mice treated with i.t. Leu-ENK alone. We also investigated the effect of the extracellular signal-regulated kinase (ERK) in spinal processing of nociception induced by i.t. co-administration of Leu-ENK with phospharamidon and bestatin. Western blot analysis of phospho-ERK (pERK) showed a significant increase of pERK2 in the lumbar spinal cord in response to i.t. Leu-ENK co-injected with peptidase inhibitors. The MAP kinase-ERK inhibitor, U0126 dose-dependently attenuated the nociceptive behavior and spinal ERK activation to i.t. Leu-ENK co-injected with peptidase inhibitors. Furthermore, the nociceptive behavior and spinal ERK activation evoked by i.t. Leu-ENK in combination with peptidase inhibitors were inhibited by co-administration of the non-selective δ-opioid receptor antagonist, naltrindole, the selective δ2-opioid receptor antagonist, naltriben, the non-competitive N-methyl-D-aspartate (NMDA) antagonist, MK-801 or the non-selective nitric oxide synthase inhibitor, L-NAME, the selective nNOS inhibitor, N(ω)-propyl-L-arginine or the selective iNOS inhibitor, W1400, but not by the selective δ1-receptor antagonist, BNTX (7-benzylidenenaltrexone). These results suggest that spontaneous nociceptive behaviors produced by i.t. co-administration of Leu-ENK with peptidase inhibitors may be induced by an activation of the glutamate-NO-ERK pathway through the δ2-opioid receptor in the dorsal spinal cord.

Topics: Animals; Arginine; Behavior, Animal; Butadienes; Enkephalin, Leucine; Enzyme Activation; Glycopeptides; Injections, Spinal; Leucine; Male; Mice, Inbred Strains; Mitogen-Activated Protein Kinase 1; Naltrexone; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitriles; Nociception; Protease Inhibitors; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid, delta; Spinal Cord

It is generally believed that NMDA receptor antagonism accounts for most of the anesthetic and analgesic effects of ketamine, however, it interacts at multiple sites in the central nervous system, including NMDA and non-NMDA glutamate receptors, nicotinic and muscarinic cholinergic receptors, and adrenergic and opioid receptors. Interestingly, it was shown that at supraspinal sites, ketamine interacts with the μ-opioid system and causes supraspinal antinociception. In this study, we investigated the involvement of endogenous opioids in ketamine-induced central antinociception. The nociceptive threshold for thermal stimulation was measured in Swiss mice using the tail-flick test. The drugs were administered via the intracerebroventricular route. Our results demonstrated that the opioid receptor antagonist naloxone, the μ-opioid receptor antagonist clocinnamox and the δ-opioid receptor antagonist naltrindole, but not the κ-opioid receptor antagonist nor-binaltorphimine, antagonized ketamine-induced central antinociception in a dose-dependent manner. Additionally, the administration of the aminopeptidase inhibitor bestatin significantly enhanced low-dose ketamine-induced central antinociception. These data provide evidence for the involvement of endogenous opioids and μ- and δ-opioid receptors in ketamine-induced central antinociception. In contrast, κ-opioid receptors not appear to be involved in this effect.

Topics: Aminopeptidases; Analgesics; Animals; Brain; Cinnamates; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hot Temperature; Ketamine; Leucine; Male; Mice; Morphine Derivatives; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptive Pain; Opioid Peptides; Pain Perception; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

We assessed the possible influence of a neuropeptide FF analogue, 1DMe ([D-Tyr(1),(NMe)Phe(3)]neuropeptide FF), on the inhibitory action of endogenous and exogenous partial differential-opioid receptor agonists on K(+)-evoked [Met(5)]-enkephalin release from superfused rat spinal cord slices. 1DMe (0.1-10 microM) dose-dependently enhanced the increase in superfusate [Met(5)]-enkephalin content due to the peptidase inhibitors thiorphan (1 microM) and bestatin (20 microM), and prevented the reduction in [Met(5)]-enkephalin release due to stimulation of partial differential receptors by 1 microM deltorphin I. Because it had the same effects as partial differential-opioid receptor antagonists, 1DMe might act through the functional blockade of presynaptically located partial differential-opioid autoreceptors.

Topics: Animals; Autoreceptors; Dose-Response Relationship, Drug; Enkephalin, Methionine; In Vitro Techniques; Leucine; Male; Naltrexone; Narcotic Antagonists; Oligopeptides; Potassium; Rats; Rats, Sprague-Dawley; Spinal Cord; Thiorphan

The antinociceptive effect of intrathecally (i.t.) administered protease inhibitors was tested against capsaicin (800 ng) injected into the dorsal surface of a hindpaw. Both p-hydroxymercuribenzoate (2-8 nmol), a cysteine protease inhibitor, and phosphoramidon (1-4 nmol), an endopeptidase 24.11 inhibitor in the presence of bestatin (0.25 nmol) an aminopeptidase inhibitor, administered i.t. 60 min prior to the injection of capsaicin produced a dose-dependent reduction of the capsaicin-induced paw licking and biting response. p-Hydroxymercuribenzoate (4 nmol)-induced antinociception was significantly antagonized by nor-binaltorphimine, a selective kappa-opioid receptor antagonist, but not by naltrindole, a selective delta-opioid receptor antagonist. On the other hand, phosphoramidon (4 nmol) /bestatin-induced antinociception was significantly antagonized by naltrindole, but not by nor-binaltorphimine. The results indicate that the antinociceptive effect of p-hydroxymercuribenzoate may be due to the inhibition of a cysteine protease degrading endogenous dynorphins whereas phosphoramidon in the presence of bestatin blocks the degradation of enkephalins.

Topics: Animals; Capsaicin; Dose-Response Relationship, Drug; Drug Combinations; Glycopeptides; Hindlimb; Hydroxymercuribenzoates; Injections, Spinal; Leucine; Male; Mice; Mice, Inbred Strains; Naltrexone; Narcotic Antagonists; Pain; Protease Inhibitors; Receptors, Opioid; Time Factors

L-Arginine produces central antinociception by acting as a precursor of kyotorphin (L-tyrosyl-L-arginine), a [Met5]enkephalin releaser. This study investigated the antinociceptive activity of L-ornithine, a metabolite of L-arginine. L-Ornithine given s.c. at 300-1000 mg/kg suppressed carrageenin-induced hyperalgesia in rats in a naloxone-reversible manner. L-Ornithine and L-arginine, when given i.c.v. at 10-100 mu g/mouse, elicited antinociception even in intact mice, the effects being abolished by naloxone or naltrindole, and potentiated by bestatin, an inhibitor of aminopeptidase and kyotorphinase. The antinociception induced by i.c.v. L-ornithine was also inhibited by i.c.v. L-leucyl-L-arginine, a kyotorphin receptor antagonist, but was resistant to intracisternal anti-kyotorphin serum. L-Tyrosyl-L-ornithine, a synthetic dipeptide, (1-10 mu g/mouse, i.c.v.), exerted kyotorphin-like antinociception in mice. These findings suggest that L-ornithine produces L-arginine-like antinociception via kyotorphin receptors. However, this effect does not appear to be mediated by kyotorphin itself, but most likely by L-tyrosyl-L-ornithine, a putative dipeptide.

Topics: Analgesia; Animals; Arginine; Carrageenan; Citrulline; Dipeptides; Dose-Response Relationship, Drug; Excipients; Hyperalgesia; Injections, Intraventricular; Leucine; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Ornithine; Pain Measurement; Protease Inhibitors; Rats

The possible existence of a feedback control by endogenous opioids of the spinal release of met-enkephalin-like material was assessed in vivo, in halothane-anesthetized rats whose intrathecal space was continuously perfused with an artificial cerebrospinal fluid supplemented with various opioid-related drugs. Both the intrathecal perfusion of the mu agonist D-Ala2-D-MePhe4-Gly-ol5-enkephalin (DAGO) (10 microM) and the delta agonist Tyr-D-Thr-Gly-Phe-Leu-Thr (DTLET) (10 microM) produced a significant inhibition of the spinal outflow of met-enkephalin-like material. The effect of DAGO, but not that of DTLET, could be prevented by naloxone (10 microM), and, conversely, the effect of DLTET, but not that of DAGO, was no longer observed in the presence of naltrindole (10 microM). Therefore naloxone and naltrindole acted as potent and selective mu and delta antagonists, respectively, when perfused at 10 microM in the intrathecal space of halothane-anesthetized rats. As expected from the lack of a tonic opioid control of spinal enkephalinergic neurones, neither naloxone nor naltrindole alone affected the spontaneous outflow of met-enkephalin-like material. However, naltrindole, but not naloxone, markedly increased the spinal overflow of met-enkephalin-like material due to intrathecal administration of either porcine calcitonin (10 microM) or the peptidase inhibitors thiorphan (10 microM) plus bestatin (20 microM). These data suggest that delta, but not mu, receptors are involved in a phasic opioid inhibitory control of the release of met-enkephalin-like material in the rat spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcitonin; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Methionine; Enkephalins; Feedback; Indoles; Injections, Spinal; Leucine; Male; Morphinans; Naloxone; Naltrexone; Oligopeptides; Radioimmunoassay; Rats; Rats, Inbred Strains; Spinal Cord; Thiorphan