norbinaltorphimine and Edema

It has been shown that inflammation of rat paws elicits accumulation of opioid peptide beta-endorphin-containing immune cells in the inflamed subcutaneous tissue, contributing to immunocyte-produced pain suppression. However, the possible mechanisms involved in the pharmacological application of beta-endorphin in rat paw inflammation have not been investigated. The present study was set up to explore the effects of intraplantar injection of beta-endorphin on Concanavalin A-induced paw edema in two inbred rat strains, Albino Oxford (AO) and Dark Agouti (DA). Both high dose-induced suppression and low dose-induced potentiation of edema development in AO and DA rats, respectively, were blocked with antagonists specific for delta (naltrindole) and kappa (nor-binaltorphimine) opioid receptors. beta-endorphin in vitro decreased phagocytosis and increased nitric oxide (NO) production in air pouch granulocytes obtained from AO rats. However, in cells from DA rat strain beta-endorphin modulated both phagocytosis and NO production in a concentration-dependent manner. It could be concluded that the strain-dependent opposing effects of beta-endorphin on paw inflammation are mediated through delta and kappa opioid receptors and probably involve changes in the production of reactive oxygen species by inflammatory cells. Our results point to the importance of genotype for pharmacological manipulations and the development of inflammation.

Topics: Animals; beta-Endorphin; Concanavalin A; Dose-Response Relationship, Drug; Edema; Female; Granulocytes; Hindlimb; Inflammation; Male; Naltrexone; Narcotic Antagonists; Neurotransmitter Agents; Nitric Oxide; Phagocytosis; Rats; Rats, Inbred Strains; Receptors, Opioid, delta; Receptors, Opioid, kappa; Species Specificity

Recent clinical studies have demonstrated that when morphine is used to control pain in cancer patients, psychological dependence is not a major concern. The present study was undertaken to ascertain the modulation of psychological dependence on morphine under a chronic pain-like state in rats. The prototypical mu-opioid receptor agonist morphine (8 mg/kg, i.p.) induced a dose-dependent place preference. In the present study, we found that an inflammatory pain-like state following formalin injection significantly suppressed the morphine-induced rewarding effect. This effect was almost reversed by s.c. pretreatment with the kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI, 5 mg/kg). Furthermore, the morphine-induced increase in dopamine (DA) turnover in the limbic forebrain was significantly inhibited by treatment with formalin. This inhibition was also suppressed by pretreatment with nor-BNI. In addition, in vivo microdialysis studies clearly showed that the morphine-induced increase in the extracellular levels of DA and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in the nucleus accumbens (N.Acc.) was significantly decreased in rats that had been pretreated with formalin. This effect was in turn reversed by the microinjection of a specific dynorphin A antibody into the N.Acc. These findings suggest that the inflammatory pain-like state induced by formalin injection may have caused a sustained activation of the kappa-opioidergic system within the N.Acc., resulting in suppression of the morphine-induced rewarding effect in rats. The present study provides further evidence of the clinical usefulness of morphine in patients suffering from severe pain.

Topics: Animals; Brain Chemistry; Conditioning, Operant; Dopamine; Dynorphins; Edema; Foot; Formaldehyde; Inflammation; Limbic System; Male; Microdialysis; Microinjections; Morphine; Naltrexone; Narcotic Antagonists; Narcotics; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Reward

The effect of intraplantarly (i.pl.)-injected methionine-enkephalin (ME) on Concanavalin A (Con A)-induced paw edema in Dark Agouti (DA) and Albino Oxford (AO) rats was investigated. ME suppressed edema in DA rats, which was antagonized with naloxone (non-selective opioid receptor antagonist) and naltrindole (delta opioid receptors antagonist). Potentiating effect of ME in AO rats was blocked by naloxone, nor-binaltorphimine (kappa opioid receptors antagonist) and beta-funaltrexamine (mu opioid receptors antagonist). Dexamethasone suppressed edema in both rat strains. These findings suggest that strain-dependent differences in the effects of ME on inflammation in DA and AO rats could be related to diversity in opioid receptors expression in these strains.

Topics: Animals; Dexamethasone; Dose-Response Relationship, Drug; Edema; Enkephalin, Methionine; Glucocorticoids; Inflammation; Kinetics; Male; Naloxone; Naltrexone; Narcotic Antagonists; Rats; Species Specificity; Time Factors

In an attempt to study the anti-inflammatory and the antinociceptive effects of a kappa1-opioid receptor agonist (U-69,593: trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl)cycloexil]benzene acetamide methanesulfonate), we used a combination of the measurement of peripheral oedema (with a calliper) and Fos immunodetection in the carrageenin model of inflammation. The intraplantar injection of carrageenin-induced the development of a peripheral oedema, associated with an increase in Fos-like immunoreactivity at the level of the dorsal horn of the spinal cord. U-69,593 administered intravenously (i.v.) 10 min before carrageenin administration over the dose range 0.75, 1.5 and 3 mg/kg, reduced both paw and ankle oedema in a non dose-dependent manner. The maximal decrease was observed at the highest dose and did not exceed 21% and 20% for the paw and the ankle respectively. These effects were kappa-opioid receptor specific since the anti-inflammatory effect of 1.5 mg/kg i.v. of U-69,593 was antagonised by a specific kappa-opioid receptor antagonist nor-binaltorphimine. Pre-treatment with U-69,593 strongly decreased the number of Fos-like Immunoreactive neurones of the spinal cord in a dose-dependent, antagonist reversible manner; maximal effect was 65%. The disparate results between the anti-inflammatory effects and the depressive effects on Fos expression suggest that anti-inflammatory effects of kappa-opioid receptor agonist are of minor importance for the antinociceptive effects of this compound.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Benzeneacetamides; Carrageenan; Dose-Response Relationship, Drug; Drug Interactions; Edema; Immunochemistry; Inflammation; Male; Naltrexone; Narcotic Antagonists; Photomicrography; Proto-Oncogene Proteins c-fos; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Spinal Cord