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


METHODS
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.


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
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.
Tanabe
M
M
Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan. mitana@phar.nagoya-cu.ac.jp
Tokuda
Y
Y
Takasu
K
K
Ono
K
K
Honda
M
M
Ono
H
H
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000700:Analgesics; D000818:Animals; D015306:Biogenic Monoamines / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D010134:Fenclonine / Q000494:pharmacology; D006358:Hot Temperature; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects; D009638:Norepinephrine / Q000502:physiology; D016627:Oxidopamine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D011930:Reaction Time / Q000187:drug effects; D012701:Serotonin / Q000502:physiology; D018490:Serotonin Agents / Q000494:pharmacology; D013565:Sympatholytics / Q000494:pharmacology; D013972:Thyrotropin / Q000031:analogs & derivatives*; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D015306:Biogenic Monoamines; D009292:Narcotic Antagonists; D018490:Serotonin Agents; D013565:Sympatholytics; C065049:TA 0910; D015016:Yohimbine; D012701:Serotonin; D009270:Naloxone; D013973:Thyrotropin-Releasing Hormone; D016627:Oxidopamine; D013972:Thyrotropin; D007650:Ketanserin; D010134:Fenclonine; D009638:Norepinephrine