The synthetic TRH analogue taltirelin exerts modality‐specific antinociceptive effects via distinct descending monoaminergic systems

Abstract

Background and purpose: Exogenously administered thyrotropin-releasing hormone (TRH) is known to exert potent but short-acting centrally-mediated antinociceptive effects. We sought to investigate the mechanisms underlying these effects using the synthetic TRH analogue taltirelin, focusing on the descending monoaminergic systems in mice. Experimental approach: The mice received systemic or local injections of taltirelin combined with either central noradrenaline (NA) or 5-hydroxytryptamine (5-HT) depletion by 6-hydroxydopamine (6-OHDA) or DL-p-chlorophenylalanine (PCPA), respectively, or blockade of their receptors. The degree of antinociception was determined using the tail flick and tail pressure tests. Key results: Subcutaneously (s.c.) administered taltirelin exhibited dose-dependent antinociceptive effects in the tail flick and tail pressure tests. These effects appeared to be primarily supraspinally mediated, since intracerebroventricularly (i.c.v.) but not intrathecally (i.t.) injected taltirelin generated similar effects. Depletion of central NA abolished only the analgesic effect of taltirelin (s.c. and i.c.v.) on mechanical nociception. By contrast, depletion of central 5-HT abolished only its analgesic effect on thermal nociception. Intraperitoneal (i.p.) and i.t. injection of the a 2 -adrenoceptor antagonist yohimbine respectively reduced the analgesic effect of taltirelin (s.c. and i.c.v.) on mechanical nociception. By contrast, the 5-HT 1A receptor antagonist WAY-100635 (i.p. and i.t.) reduced the effect of taltirelin (s.c. and i.c.v.) on thermal nociception. Neither the 5-HT 2 receptor antagonist ketanserin nor the opioid receptor antagonist naloxone altered the antinociceptive effect of taltirelin. Conclusions and Implications: These findings suggest that taltirelin activates the descending noradrenergic and serotonergic pain inhibitory systems, respectively, to exert its analgesic effects on mechanical and thermal nociception.

Presynaptic Inhibitory Effects of Fluvoxamine, a Selective Serotonin Reuptake Inhibitor, on Nociceptive Excitatory Synaptic Transmission in Spinal Superficial Dorsal Horn Neurons of Adult Mice

“…1), keeping in mind that both pronociceptive and antinociceptive roles have been demonstrated for spinal 5-HT 1A and 5-HT 3 receptors (15). Nevertheless, although we focused only on monosynaptic nociceptive synaptic transmission in the spinal dorsal horn, the present electrophysiological and pharmacological experiments employing specific antagonists of 5-HT 1A and 5-HT 3 receptors may at least partly support our previous behavioral studies that addressed the relationship between endogenously released 5-HT and receptor subtypes mediating its antinociceptive effects assessed using acute heat and mechanical stimuli; the analgesic effect of fluvoxamine on acute mechanical nociception was mediated by 5-HT 3 receptors (4), and the analgesic effect on acute thermal nociception, driven by the bulbospinal 5-HT pathways upon administration of the TRH analogue taltirelin, was mediated by 5-HT 1A receptors (22). In addition, 5-HT 3 receptors have been shown to be involved in the antinociceptive effect of the SSRI paroxetine on acute nociception elicited by thermal stimuli (33).…”

“…In addition, we also revealed that spinal 5-HT 1A receptors mediated the analgesic effects on acute thermal nociception, driven by the bulbospinal 5-HT pathways upon administration of the thyrotropin-releasing hormone (TRH) analogue taltirelin (22). Therefore, WAY100635 and tropisetron, a 5-HT 1A receptor antagonist and a 5-HT 3 receptor antagonist, respectively, were employed to assess whether these receptor subtypes mediated the fluvoxamine-induced suppression of monosynaptic Afiber-and C-fiber-mediated EPSCs.…”

The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception

“…We focused on TRHDE, because it has been reported that TRH, the substrate for TRHDE, can affect pain in human and rodents. [29][30][31] Moreover, we found that TRH is strongly upregulated in our Prdm12 overexpressing RA treated neuralized caps, 8 a result validated by RTqPCR (Fig. 1A).…”

Serotonergic System Does Not Contribute to the Hypothermic Action of Acetaminophen

“…17) The inhibitory effect of PCPA on AcAP-induced analgesia in the formalin test is also consistent with the results of an earlier study. 7) Consistent with previous reports, 30,31) the PCPA treatment protocol used in the present study markedly reduced the serotonin content of the central nervous system. The basal rectal temperature of the PCPAtreated mice was normal, suggesting that the lack of serotonin can be compensated by other thermoregulatory mechanisms.…”

“…was administered for five consecutive days. 30) PCPA was suspended in 0.5% carboxymethylcellulose sodium solution (CMC). Control mice were injected with CMC alone.…”