urb-597 and Nociceptive-Pain

Clinical studies have demonstrated that the NMDA receptor antagonist ketamine produces rapid antidepressant responses. There are safety concerns and adverse effects that limit the utilization of ketamine in psychiatry. Some studies have suggested combination therapy for optimal ketamine use. In this study, we evaluated the potential for combination therapy of ineffective doses of ketamine and fatty acid amide hydrolase inhibitor URB597 for the treatment of depression and pain in male NMRI mice. Intraperitoneal administration of ketamine (10 mg/kg) at the time intervals of 115, 145, and 160 min and ketamine (5 mg/kg) at the time interval of 160 min after administration increased the tail-flick latency, indicating an antinociceptive effect. The same doses of ketamine decreased immobility time in the forced swim test (FST), showing an antidepressant-like effect. Moreover, URB597 at the doses of 0.5 and 1 mg/kg induced an antinociceptive effect, while it at the dose of 1 mg/kg produced an antidepressant-like response. Furthermore, co-administration of the ineffective doses of ketamine (2.5 mg/kg) and URB597 (0.1 mg/kg) caused antinociceptive and antidepressant-like effects, while each one of them alone did not alter the performance of mice in the FST and tail-flick tests. It should be noted that none of the treatments alter animal locomotor activity compared to the control group. Therefore, the combined administration of ineffective doses of ketamine and URB597 might be an effective strategy in the therapy of depression and pain.

Topics: Amidohydrolases; Analgesics; Animals; Antidepressive Agents; Behavior, Animal; Benzamides; Carbamates; Dose-Response Relationship, Drug; Drug Synergism; Ketamine; Male; Mice, Inbred Strains; Motor Activity; Nociceptive Pain; Receptors, N-Methyl-D-Aspartate; Swimming

Aberrant activation of toll-like receptor (TLR)s results in persistent and prolonged neuroinflammation and has been implicated in the pathogenesis and exacerbation of psychiatric and neurodegenerative disorders. TLR3 coordinates the innate immune response to viral infection and recent data have demonstrated that inhibiting fatty acid amide hydrolase (FAAH), the enzyme that primarily metabolizes anandamide, modulates TLR3-mediated neuroinflammation. However, the physiological and behavioural consequences of such modulation are unknown. The present study examined the effect of URB597, a selective FAAH inhibitor, on neuroinflammation, physiological and behavioural alterations following administration of the TLR3 agonist and viral mimetic poly I:C to female rats. URB597 attenuated TLR3-mediated fever, mechanical and cold allodynia, and anxiety-like behaviour in the elevated plus maze and open field arena. There was no effect of URB597 on TLR3-mediated decreases in body weight and no effect in the sucrose preference or forced swim tests. URB597 attenuated the TLR3-mediated increase in the expression of CD11b and CD68, markers of microglia/macrophage activation. In summary, these data demonstrate that enhancing FAAH substrate levels suppresses TLR3-mediated microglia/macrophage activation and associated changes in fever, nociceptive responding and anxiety-related behaviour. These data provide further support for FAAH as a novel therapeutic target for neuroinflammatory disorders.

Topics: Amidohydrolases; Animals; Anxiety; Benzamides; Carbamates; Central Nervous System Agents; Enzyme Inhibitors; Fever; Hypothalamus; Inflammation; Macrophages; Microglia; Nociceptive Pain; Random Allocation; Rats; Rats, Sprague-Dawley; Toll-Like Receptor 3