sb-334867-a and Nociceptive-Pain

In this study, we investigated the effect of long-term administration of orexin receptor 1 (OXR1) antagonist on naloxone-precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine-dependent rats.. Wistar rats received subcutaneous (s.c.) injections of morphine (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 h for 7 days. In chronic groups, the OXR1 antagonist, SB-334867 (20 mg/kg, i.p.), or its vehicle, was injected repetitively from postnatal day 1 (PND1)-PND23 and then for the following seven days before each morphine injection. Meanwhile, in acute groups, SB-334867, or its vehicle, was administered before each morphine injection. In groups of rats that were designated for withdrawal experiments, naloxone (2.5 mg/kg, i.p.) was administered after the last injection of morphine. In the formalin-induced pain, the effect of OXR1 inhibition on the antinociceptive effects of morphine was measured by injecting formalin after the final morphine injection.. Animals that received long-term SB-334867 administration before morphine injection demonstrated a significant reduction in chewing, defecation, diarrhea, grooming, teeth chattering, wet-dog shake, and writhing. Inhibiting OXR1 for a long time increased formalin-induced nociceptive behaviors in interphase and phase II of the formalin-induced pain.. Our results indicated that the inhibition of OXR1 significantly reduces the development of morphine dependence and behavioral signs elicited by the administration of naloxone in morphine-dependent rats. Furthermore, the prolonged blockade of OXR1 might be involved in formalin-induced nociceptive behaviors.

Topics: Animals; Behavior, Animal; Benzoxazoles; Disease Models, Animal; Morphine; Morphine Dependence; Naloxone; Naphthyridines; Narcotic Antagonists; Narcotics; Nociceptive Pain; Orexin Receptor Antagonists; Rats; Rats, Wistar; Substance Withdrawal Syndrome; Urea

The Hippocampus has a role not only in nociception but also in modulation of pain perception. In addition, orexinergic neurons present in the lateral hypothalamus (LH) have a recognized role in pain modulation. The presence of orexinergic projections from the lateral hypothalamus (LH) to the dorsal hippocampal Cornu Ammonis 1 (CA1) region raises the question of whether pain modulatory role of LH is mediated through the CA1. To elucidate the interactions between the LH and neural substrates involved in modulation of formalin-induced nociception, the study aimed to test the pain modulatory role of CA1 orexin receptors in the formalin test. Seventy-one male Wistar rats were unilaterally implanted with two cannulae above the LH and CA1. In the treatment groups, intra-CA1 administration of SB-334867, as an orexin-1 receptor antagonist, was performed 5min before intra-LH microinjection of carbachol, as a cholinergic receptor agonist. In dimethyl sulfoxide (DMSO)-control group, DMSO and saline as well as in carbachol-control group, DMSO and carbachol were microinjected into the CA1 and LH, respectively. In all rats, the procedure was followed by subcutaneous injection of formalin after 5-min time interval. Carbachol reduced both phases of formalin-induced nociception. Intra-CA1 administration of SB-334867 antagonized the LH-induced analgesia during both phases in a dose-dependent manner. It seems that the blockade of orexin-1 receptors has more effects on reduction of antinociception during the late phase compared to the early phase. Pain modulatory role of orexinergic system in the formalin test through a neural pathway from the LH to CA1 provides the evidence that orexins can be useful therapeutic agents for chronic pain treatment.

Topics: Analgesics; Animals; Benzoxazoles; CA1 Region, Hippocampal; Carbachol; Catheters, Indwelling; Cholinergic Agonists; Dose-Response Relationship, Drug; Formaldehyde; Hypothalamic Area, Lateral; Inflammation; Male; Naphthyridines; Nociceptive Pain; Orexin Receptor Antagonists; Orexin Receptors; Pain Perception; Rats, Wistar; Stimulation, Chemical; Urea

The orexin system consists of orexin A/hypocretin 1 and orexin B/hypocretin 2, and OX1 and OX2 receptors. Our previous electrophysiological study showed that orexin A in the rat ventrolateral periaqueductal gray (vlPAG) induced antinociception via an OX1 receptor-initiated and endocannabinoid-mediated disinhibition mechanism. Here, we further characterized antinociceptive effects of orexins in the mouse vlPAG and investigated whether this mechanism in the vlPAG can contribute to stress-induced analgesia (SIA) in mice. Intra-vlPAG (i.pag.) microinjection of orexin A in the mouse vlPAG increased the hot-plate latency. This effect was mimicked by i.pag. injection of WIN 55,212-2, a CB1 agonist, and antagonized by i.pag. injection of the antagonist of OX1 (SB 334867) or CB1 (AM 251), but not OX2 (TCS-OX2-29) or opioid (naloxone), receptors. [Ala(11), D-Leu(15)]-orexin B (i.pag.), an OX2 selective agonist, also induced antinociception in a manner blocked by i.pag. injection of TCS-OX2-29, but not SB 334867 or AM 251. Mice receiving restraint stress for 30 min showed significantly longer hot-plate latency, more c-Fos-expressing orexin neurons in the lateral hypothalamus and higher orexin levels in the vlPAG than unrestrained mice. Restraint SIA in mice was prevented by i.pag. or intraperitoneal injection of SB 334867 or AM 251, but not TCS-OX2-29 or naloxone. These results suggest that during stress, hypothalamic orexin neurons are activated, releasing orexins into the vlPAG to induce analgesia, possibly via the OX1 receptor-initiated, endocannabinoid-mediated disinhibition mechanism previously reported. Although activating either OX1 or OX2 receptors in the vlPAG can lead to antinociception, only OX1 receptor-initiated antinociception is endocannabinoid-dependent.

Topics: Analgesics, Opioid; Animals; Benzoxazines; Benzoxazoles; Corticosterone; Hypothalamus; Isoquinolines; Male; Mice, Inbred C57BL; Morpholines; Naloxone; Naphthalenes; Naphthyridines; Neurons; Nociceptive Pain; Orexin Receptors; Pain Perception; Periaqueductal Gray; Proto-Oncogene Proteins c-fos; Pyridines; Receptor, Cannabinoid, CB1; Signal Transduction; Stress, Psychological; Urea