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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 alpha2-adrenoceptor antagonist yohimbine respectively reduced the analgesic effect of taltirelin (s.c. and i.c.v.) on mechanical nociception. By contrast, the 5-HT1A 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-HT2 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.

SUBMITTER: Tanabe M

PROVIDER: S-EPMC2189720 | biostudies-other | 2007 Feb

REPOSITORIES: biostudies-other

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Project description:The formation of mature spinal motor circuits is dependent on both activity-dependent and independent mechanisms during postnatal development. During this time, reorganization and refinement of spinal sensorimotor circuits occurs as supraspinal projections are integrated. However, specific features of postnatal spinal circuit development remain poorly understood. This study provides the first detailed characterization of rat spinal sensorimotor circuit development in the presence and absence of descending systems. We show that the development of proprioceptive afferent input to motoneurons (MNs) and Renshaw cells (RCs) is disrupted by thoracic spinal cord transection at postnatal day 5 (P5TX). P5TX also led to malformation of GABApre neuron axo-axonic contacts on Ia afferents and of the recurrent inhibitory circuit between MNs and RCs. Using a novel in situ perfused preparation for studying motor control, we show that malformation of these spinal circuits leads to hyperexcitability of the monosynaptic reflex. Our results demonstrate that removing descending input severely disrupts the development of spinal circuits and identifies key mechanisms contributing to motor dysfunction in conditions such as cerebral palsy and spinal cord injury.SIGNIFICANCE STATEMENT Acquisition of mature behavior during postnatal development correlates with the arrival and maturation of supraspinal projections to the spinal cord. However, we know little about the role that descending systems play in the maturation of spinal circuits. Here, we characterize postnatal development of key spinal microcircuits in the presence and absence of descending systems. We show that formation of these circuits is abnormal after early (postnatal day 5) removal of descending systems, inducing hyperexcitability of the monosynaptic reflex. The study is a detailed characterization of spinal circuit development elucidating how these mechanisms contribute to motor dysfunction in conditions such as cerebral palsy and spinal cord injury. Understanding these circuits is crucial to developing new therapeutics and improving existing ones in such conditions.

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

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