Tuberoinfundibular peptide of 39 residues (TIP39) signaling modulates acute and tonic nociception.
Tuberoinfundibular peptide of 39 residues (TIP39) synthesizing neurons at the caudal border of the thalamus and in the lateral pons project to areas rich in its receptor, the parathyroid hormone 2 receptor (PTH2R). These areas include many involved in processing nociceptive information. Here we examined the potential role of TIP39 signaling in nociception using a PTH2R antagonist (HYWH) and mice with deletion of TIP39's coding sequence or PTH2R null mutation. Intracerebroventricular (icv) infusion of HYWH significantly inhibited nociceptive responses in tail-flick and hot-plate tests and attenuated the nociceptive response to hindpaw formalin injection. TIP39-KO and PTH2R-KO had increased response latency in the 55°C hot-plate test and reduced responses in the hindpaw formalin test. The tail-flick test was not affected in either KO line. Thermal hypoalgesia in KO mice was dose-dependently reversed by systemic administration of the cannabinoid receptor 1 (CB1) antagonist rimonabant, which did not affect nociception in wild-type (WT). Systemic administration of the cannabinoid agonist CP 55,940 did not affect nociception in KO mice at a dose effective in WT. WT mice administered HYWH icv, and both KOs, had significantly increased stress-induced analgesia (SIA). Rimonabant blocked the increased SIA in TIP39-KO, PTH2R-KO or after HYWH infusion. CB1 and FAAH mRNA were decreased and increased, respectively, in the basolateral amygdala of TIP39-KO mice. These data suggest that TIP39 signaling modulates nociception, very likely by inhibiting endocannabinoid circuitry at a supraspinal level. We infer a new central mechanism for endocannabinoid regulation, via TIP39 acting on the PTH2R in discrete brain regions.
Dimitrov
Eugene L
EL
Section on Fundamental Neuroscience, National Institute of Mental Health, 35 Convent Drive, Room 1B-213, Bethesda, MD 20892, USA. dimitrove@mail.nih.gov
Petrus
Emily
E
Usdin
Ted B
TB
D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D005557:Formaldehyde; D017403:In Situ Hybridization; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009479:Neuropeptides / Q000008:administration & dosage / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000473:pathology / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D044183:Receptor, Parathyroid Hormone, Type 2 / Q000096:biosynthesis / Q000235:genetics; D000077285:Rimonabant; D015398:Signal Transduction / Q000502:physiology*; D013315:Stress, Psychological / Q000523:psychology; D013569:Synapses / Q000502:physiology; D050599:Vesicular Glutamate Transport Protein 2 / Q000096:biosynthesis / Q000235:genetics; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D005557:Formaldehyde; D009270:Naloxone; D009292:Narcotic Antagonists; D009479:Neuropeptides; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D044183:Receptor, Parathyroid Hormone, Type 2; D000077285:Rimonabant; D050599:Vesicular Glutamate Transport Protein 2; D000099252:Fatty Acid Amide Hydrolases; C493477:Slc17a6 protein, mouse; C400136:tuberoinfundibular peptide 39