1-3-dihydroxy-4-4-5-5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole and Pain

Previous research has found that hyperbaric oxygen (HBO(2)) produces an acute antinociceptive effect that is dependent on nitric oxide (NO). The present study was undertaken to determine whether HBO(2)-induced acute antinociception might involve a NO-cyclic GMP-protein kinase G-ATP-sensitive potassium (K(ATP)) channel pathway. Male NIH Swiss mice were subjected to a 5-min HBO(2) treatment (100% oxygen at 3.5 absolute atmospheres) and antinociception was assessed over the next 6 min still under HBO(2) using the acetic acid abdominal constriction test. Pretreatment with 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO, an NO scavenger), 1H-[1,2,4]-oxadiazolo-[4,3-a]quinoxalin-1-one) (a soluble guanylyl cyclase-inhibitor, Rp-8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate (a protein kinase G-inhibitor) or glibenclamide (an ATP-sensitive potassium channel-inhibitor) all led to antagonism of the HBO(2)-induced acute antinociception in a dose-dependent manner. These findings suggest that HBO(2)-induced acute antinociception might be due to activation of a NO-cyclic GMP-protein kinase G-K(ATP) channel pathway.

Topics: Acetic Acid; Animals; Benzoates; Cyclic GMP-Dependent Protein Kinases; Glyburide; Guanylate Cyclase; Hyperbaric Oxygenation; Imidazoles; KATP Channels; Male; Metabolic Networks and Pathways; Mice; Models, Animal; Nitric Oxide; Pain; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Treatment Outcome

Nitric oxide (NO) has been reported to enhance the analgesic effect of the peripherally administered mu-opioid receptor agonists, but the role of NO on the analgesic effect of the peripherally administered kappa and delta opioid receptor agonists is still unclear. We examined the effects of peripherally applied kappa- and delta-opioid receptor agonists and of their interactions with the NO-releasing drug, FK409, on the behavioral response to intraplantar injection of formalin in rats (the formalin test). The formalin injection results in a biphasic appearance of agitation behavior, consisting of the early (Phase 1; 0-9 min) and late (Phase 2; 10-60 min) responses. The active enantiomer of kappa-opioid receptor agonist, (-)U50,488H, dose-dependently suppressed the agitation response in both phases of the formalin test when applied peripherally. A peripheral delta-opioid receptor agonist, [D-Pen(2,5)] enkephalin (DPDPE), suppressed only Phase 2 of the formalin test. Local application of FK409 after the administration of a subthreshold dose of each opioid resulted in a dose-dependent decrease in the Phase 1, but not Phase 2, response to the formalin test for both agonists. Interactions between peripheral opioids and FK409 were reversed with both naloxone and carboxy-PTIO (NO scavenger). Systemic injections of either a kappa- or delta-agonist had no interaction with peripherally applied FK409. Peripheral FK409 alone did not have any significant effect on the formalin test. These data indicate that the antinociceptive effects of peripherally applied kappa- and delta-opioid agonists on the formalin test are potentiated by the local action of NO.. The analgesic effects of peripherally applied kappa- and delta-opioid receptor agonists during inflammation induced by formalin injection in the rat are, at least partly, mediated by the NO-cGMP pathway.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzoates; Dose-Response Relationship, Drug; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Formaldehyde; Imidazoles; Male; Nitric Oxide; Nitro Compounds; Pain; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa