title: Group II/III metabotropic glutamate receptors exert endogenous activity-dependent modulation of TRPV1 receptors on peripheral nociceptors.
abstract: There is pharmacological evidence that group II and III metabotropic glutamate receptors (mGluRs) function as activity-dependent autoreceptors, inhibiting transmission in supraspinal sites. These receptors are expressed by peripheral nociceptors. We investigated whether mGluRs function as activity-dependent autoreceptors inhibiting pain transmission to the rat CNS, particularly transient receptor potential vanilloid 1 (TRPV1)-induced activity. Blocking peripheral mGluR activity by intraplantar injection of antagonists LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid] (LY) (20, 100 μm, group II/III), APICA [(RS)-1-amino-5-phosphonoindan-1-carboxylic acid] (100 μm, group II), or UBP1112 (α-methyl-3-methyl-4-phosphonophenylglycine) (30 μm, group III) increased capsaicin (CAP)-induced nociceptive behaviors and nociceptor activity. In contrast, group II agonist APDC [(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate] (0.1 μm) or group III agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP-4) (10 μm) blocked the LY-induced increase. Ca(2+) imaging in dorsal root ganglion (DRG) cells confirmed LY enhanced CAP-induced Ca(2+) mobilization, which was blocked by APDC and l-AP-4. We hypothesized that excess glutamate (GLU) released by high intensity and/or prolonged stimulation endogenously activated group II/III, dampening nociceptor activation. In support of this, intraplantar GLU + LY produced heat hyperalgesia, and exogenous GLU + LY applied to nociceptors produced enhanced nociceptor activity and thermal sensitization. Intraplantar Formalin, known to elevate extracellular GLU, enhanced pain behaviors in the presence of LY. LY alone produced no pain behaviors, no change in nociceptor discharge rate or heat-evoked responses, and no change in cytosolic Ca(2+) in DRG cells, demonstrating a lack of tonic inhibitory control. Group II/III mGluRs maintain an activity-dependent autoinhibition, capable of significantly reducing TRPV1-induced activity. They are endogenously activated after high-frequency and/or prolonged nociceptor stimulation, acting as built-in negative modulators of TRPV1 and nociceptor function, reducing pain transmission to the CNS.
authors: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1069, USA. smcarlto@utmb.edu
authors: Susan M
authors: SM
authors: Carlton
authors: Shengtai
authors: S
authors: Zhou
authors: Rosann
authors: R
authors: Govea
authors: Junhui
authors: J
authors: Du
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005557:Formaldehyde; D018698:Glutamic Acid / Q000378:metabolism; D006358:Hot Temperature; D008297:Male; D009619:Nociceptors / Q000502:physiology*; D010146:Pain / Q000139:chemically induced; D010147:Pain Measurement / Q000187:drug effects; D017933:Peripheral Nervous System / Q000502:physiology*; D011392:Proline / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D012867:Skin / Q000294:innervation; D050916:TRPV Cation Channels / Q000187:drug effects / Q000502:physiology*; D014966:Xanthenes / Q000494:pharmacology
chemical_list: C120942:1,4-diaminopyrrolidine-2,4-dicarboxylic acid; D000596:Amino Acids; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D018094:Receptors, Metabotropic Glutamate; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014966:Xanthenes; D005557:Formaldehyde; D018698:Glutamic Acid; D011392:Proline; D002211:Capsaicin; D002118:Calcium