n-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide and Neuralgia

Topics: Aminoquinolines; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Benzamides; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Humans; Narcotic Antagonists; Neuralgia; Nitric Oxide; Nociceptin; Nociceptin Receptor; Opioid Peptides; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Spinal Cord

Chemotherapy-induced peripheral neuropathy is a serious adverse effect of chemotherapeutic agents such as paclitaxel. JTC-801, a nociceptin/orphanin FQ opioid peptide (NOP) receptor antagonist, has been reported to attenuate neuropathic pain in several pain models. However, the therapeutic significance and function of JTC-801 in chemotherapy-induced peripheral neuropathy remain unclear. In this study, we determined the effect of JTC-801 on neuropathic pain induced by paclitaxel, and we explored the potential mechanism in the dorsal root ganglion (DRG). The behavioral test showed that single or multiple systemic administrations of JTC-801 significantly alleviated mechanical allodynia in paclitaxel-treated rats. Using Western blot analysis and immunohistochemistry, we found that paclitaxel increased the expression of phosphatidylinositol 3-kinase (PI3K) and phospho-Akt (p-Akt) in the DRG. Double immunofluorescence staining indicated that p-Akt was expressed in neurons in the DRG. Multiple injections of JTC-801 significantly inhibited the activation of Akt and decreased the expression of inflammatory cytokines. The data suggest that JTC-801 alleviates mechanical allodynia associated with paclitaxel-induced neuropathic pain via the PI3K/Akt pathway.

Topics: Aminoquinolines; Analgesics; Animals; Behavior, Animal; Benzamides; Disease Models, Animal; Ganglia, Spinal; Hyperalgesia; Inflammation Mediators; Interleukin-1beta; Male; Narcotic Antagonists; Neuralgia; Nociceptin Receptor; Paclitaxel; Pain Threshold; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptors, Opioid; Signal Transduction; Tumor Necrosis Factor-alpha

Combinations of analgesics from different classes are commonly used in the management of chronic pain. The goal is to enhance pain relief together with the reduction of side effects. The present study was undertaken to examine the anti-allodynic synergy resulting from the combination of WIN 55,212-2, a cannabinoid CB1 receptor agonist, and JTC-801, a nociceptin/orphanin FQ receptor antagonist, on neuropathic pain. Mice were tested for behavioral effects before and 2-4 weeks after the surgery, in which a partial tight ligation of the sciatic nerve was made. Nerve injury-induced mechanical allodynia was assessed with Dynamic Plantar Aesthesiometer, and a hot/cold plate was used to assess cold allodynia. Both WIN 55,212-2 and JTC-801 produced dose-dependent mechanical and cold anti-allodynic effects. As shown by isobolographic analysis, WIN 55,212-2/JTC-801 combinations interacted synergistically at all three ratios studied in the mechanical allodynia assay. In conclusion, co-administration of a cannabinoid with a nociceptin/orphanin FQ receptor antagonist resulted in a synergistic interaction, which may have utility in the pharmacological treatment of neuropathic pain.

Topics: Aminoquinolines; Analgesics; Animals; Benzamides; Benzoxazines; Chronic Disease; Cold Temperature; Dose-Response Relationship, Drug; Drug Synergism; Hot Temperature; Hyperalgesia; Ligation; Male; Mice; Mice, Inbred BALB C; Morpholines; Naphthalenes; Neuralgia; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain Measurement; Receptors, Cannabinoid; Receptors, Opioid; Sciatica

Pain often outlasts its usefulness as warning and aid in wound healing, and becomes chronic and intractable after tissue damage and nerve injury. Many molecules have been implicated as mediators and modulators in persistent pain such as hyperalgesia and tactile pain (allodynia). We previously showed that prostaglandin (PG) E(2), PGF(2alpha) or the neuropeptide nociceptin, also called orphanin FQ (N/OFQ) administered intrathecally (i.t.) produced allodynia in conscious mice. In the present study, we examined the relationship of pain responses between PGs and N/OFQ using the N/OFQ receptor (NOP) antagonist, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxy-methyl)benzamide monohydrochloride (JTC-801), and in mice lacking the N/OFQ prepropeptide (ppN/OFQ(-/-)) and the NOP receptor (NOP(-/-)). JTC-801 dose-dependently blocked the N/OFQ- and PGE(2)-induced allodynia, but not the PGF(2alpha)-induced one. Neither N/OFQ nor PGE(2) induced allodynia in NOP(-/-) mice. By contrast, the N/OFQ-induced allodynia was not affected by inhibition of PG production by a 60-min pretreatment with the non-steroidal anti-inflammatory drug, indomethacin. Among PGE receptor (EP) subtype-selective agonists, the EP4 agonist, AE1-329, markedly stimulated the release of N/OFQ from spinal slices and induced allodynia. AE1-329 also increased nitric oxide production in spinal slices using fluorescent nitric oxide detection, which was blocked by pretreatment with JTC-801. Conversely, PGE(2)-induced allodynia was not observed in ppN/OFQ(-/-) mice. N/OFQ immunoreactive puncta were colocalized with EP4. Taken together, these results demonstrate that PGE(2) induced allodynia by stimulation of N/OFQ release in the spinal cord via EP4 receptor subtypes.

Topics: Aminoquinolines; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Benzamides; Dinoprostone; Drug Interactions; Hyperalgesia; Immunohistochemistry; In Vitro Techniques; Indomethacin; Injections, Intraventricular; Male; Mice; Mice, Knockout; Neuralgia; Nitric Oxide; Nociceptin; Nociceptin Receptor; Opioid Peptides; Pain Measurement; Receptors, Opioid; Spinal Cord; Teprotide; Time Factors; Touch

At the spinal level, the involvement of nociceptin/orphanin FQ (N/OFQ) in pain transmission is controversial. JTC-801, a selective nonpeptidergic N/OFQ antagonist, is a good tool to examine the involvement of endogenous N/OFQ in pathophysiological conditions. In the present study, we studied the effect of JTC-801 on neuropathic pain induced by L5 spinal nerve transection in mice. Thermal hyperalgesia was evident on day 3 postsurgery and maintained during the 10-day experimental period. Oral administration of JTC-801 relieved the thermal hyperalgesia in neuropathic mice in a dose-dependent manner. Following L5 nerve transection, the increase in nitric oxide synthase (NOS) activity was observed in the superficial layer of dorsal horn and around the central canal in the spinal cord by NADPH diaphorase histochemistry. Using the novel fluorescent nitric oxide (NO) detection dye diaminofluorescein-FM, we confirmed that NO production increased in the spinal slice prepared from neuropathic mice and that the increase was more prominent in the ipsilateral side to the nerve transection than in the contralateral side. These increases in NOS activity and NO production in neuropathic mice were blocked by pretreatment of oral JTC-801. Although intraperitoneal injection of the nonselective NOS inhibitor NG.-nitro-L-arginine methyl ester transiently, but significantly, attenuated neuropathic hyperalgesia, inducible NOS-deficient mice showed neuropathic pain after L5 spinal nerve transection. These results suggest that N/OFQ is involved in the maintenance of neuropathic pain and that the analgesic effect of JTC-801 on neuropathic pain is mediated by inhibition of NO production by neuronal NOS.

Topics: Aminoquinolines; Animals; Benzamides; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Fluorescein; Fluorescence; Fluorescent Dyes; Functional Laterality; Glutamic Acid; Hyperalgesia; In Vitro Techniques; Male; Mice; Mice, Knockout; NADPH Dehydrogenase; Neuralgia; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nociceptin; Opioid Peptides; Peptide Fragments; Reaction Time; Spinal Cord; Spinal Cord Injuries; Time Factors