Parathyroid hormone 2 receptor is a functional marker of nociceptive myelinated fibers responsible for neuropathic pain.
We have previously demonstrated that parathyroid hormone 2 (PTH2) receptors are expressed in dorsal root ganglion (DRG) neurons and that its endogenous agonist tuberoinfundibular peptide of 39 residues (TIP39) causes nociceptive paw flexor responses after intraplantar administration. Here we found that the PTH2 receptor is selectively localized on myelinated A-, but not unmyelinated C-fibers using immunohistochemical labeling, based on PTH2 receptor expression on antibody N52-positive medium/large-sized DRG neurons, but not on TRPV1, substance P, P2X(3) receptor or isolectin B4-binding protein-positive small-sized DRG neurons. Pharmacological studies showed that TIP39-induced nociceptive responses were mediated by activation of G(s) and cAMP-dependent protein kinase. We also found that nociceptive responses induced by TIP39- or the cAMP analog 8-bromo-cAMP were significantly greater following partial sciatic nerve injury induced neuropathic pain, without changes in PTH2 receptor expression. Together these data suggest that activation of PTH2 receptors stimulates nociceptive A-fiber through G(s)-cAMP-dependent protein kinase signaling, and this pathway has elevated sensitization following nerve injury.
Matsumoto
Misaki
M
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Kondo
Saori
S
Usdin
Ted B
TB
Ueda
Hiroshi
H
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D010147:Pain Measurement / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D044183:Receptor, Parathyroid Hormone, Type 2 / Q000172:deficiency / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects; D012585:Sciatica / Q000473:pathology* / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D050916:TRPV Cation Channels / Q000378:metabolism; D013997:Time Factors
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009479:Neuropeptides; D010880:Piperidines; D044183:Receptor, Parathyroid Hormone, Type 2; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C400136:tuberoinfundibular peptide 39; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D002211:Capsaicin