title: Tuberoinfundibular peptide of 39 residues (TIP39) signaling modulates acute and tonic nociception.
abstract: 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.
authors.affiliation: Section on Fundamental Neuroscience, National Institute of Mental Health, 35 Convent Drive, Room 1B-213, Bethesda, MD 20892, USA. dimitrove@mail.nih.gov
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Dimitrov
authors.forename: Emily
authors.initials: E
authors.lastname: Petrus
authors.forename: Ted B
authors.initials: TB
authors.lastname: Usdin
mesh_terms: 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
chemical_list: 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