fk-409 and Pain

Pain consists of sensory and affective components. Although the neuronal mechanisms underlying the sensory component of pain have been studied extensively, those underlying its affective component are only beginning to be elucidated. Previously, we showed the pivotal role of the ventral part of the bed nucleus of the stria terminalis (vBNST) in the negative affective component of pain. Here, we examined the role of glutamate-nitric oxide (NO) signaling in the affective component of pain in rats using a conditioned place aversion (CPA) test. Intra-vBNST injection of either CNQX (an AMPA receptor antagonist) or MK-801 (an NMDA receptor antagonist) dose-dependently attenuated intraplantar formalin-induced CPA (F-CPA) without reducing nociceptive behaviors. In vivo microdialysis showed that extracellular oxidative NO metabolites (NOx) levels were significantly increased by intraplantar formalin injection. Intra-vBNST injection of NPLA (a selective neuronal NO synthase (nNOS) inhibitor), c-PTIO (a NO scavenger), or ZL006 (a postsynaptic density-95 (PSD-95)-nNOS interaction inhibitor) dose-dependently suppressed F-CPA without attenuating nociceptive behaviors. Intra-vBNST injection of NOR3 (a NO donor) produced CPA in a dose-dependent manner in the absence of noxious stimulation. Furthermore, whole-cell patch-clamp electrophysiology in the vBNST slices revealed that NOR3 induced depolarization of hyperpolarization-activated cation current (I

Topics: Animals; Conditioning, Operant; Cyclic N-Oxides; Disease Models, Animal; Excitatory Postsynaptic Potentials; Formaldehyde; Free Radical Scavengers; Hydroxylamines; Imidazoles; Male; Membrane Potentials; Neurons; Nitric Oxide Synthase Type I; Nitro Compounds; Pain; Pain Management; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Septal Nuclei; Signal Transduction

Nitric oxide (NO) may play an important role in central and peripheral nociceptive processes. However, its contribution to peripheral antinociception is still not clear. In the present study, we investigated the effect of peripherally administered FK409, a spontaneous NO releaser, and its interaction with peripheral morphine analgesia during the rat formalin test. Intraplantar injection of formalin resulted in a biphasic appearance of flinching behavior (Phase 1 = 0-9 min, Phase 2 = 10-60 min). First, an intraplantar injection of FK409 was given 5 min before the formalin injection to test for its effect alone. In the next experiment, morphine was administered first, followed 15 min later by the phosphate buffer (pH 6.0) or FK409 injection, and 5 min later by the formalin injection. FK409 alone had no effect on the number of flinches in either phase. However, when administered after intraplantar morphine, FK409 dose-dependently depressed the agitation behavior in both phases. It shifted the dose-response curve of morphine to the left. Naloxone and carboxy-PTIO (an NO scavenger) each reversed the suppressant effect of morphine and FK409 given together. These data suggest that NO enhances the analgesic effect of peripherally administered morphine in the formalin test.. Peripherally administered nitric oxide itself has no analgesic effect, but it enhances the analgesic effects of peripherally administered morphine during inflammation induced by paw formalin injection in the rat.

Topics: Animals; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Formaldehyde; Inflammation; Injections, Subcutaneous; Male; Morphine; Nitric Oxide; Nitro Compounds; Pain; Rats; Rats, Sprague-Dawley

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