title: The Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueductal Gray.
abstract: Emerging evidence indicates the involvement of GPR55 and its proposed endogenous ligand, lysophosphatidylinositol (LPI), in nociception, yet their role in central pain processing has not been explored. Using Ca(2+) imaging, we show here that LPI elicits concentration-dependent and GPR55-mediated increases in intracellular Ca(2+) levels in dissociated rat periaqueductal gray (PAG) neurons, which express GPR55 mRNA. This effect is mediated by Ca(2+) release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptors and by Ca(2+) entry via P/Q-type of voltage-gated Ca(2+) channels. Moreover, LPI depolarizes PAG neurons and upon intra-PAG microinjection, reduces nociceptive threshold in the hot-plate test. Both these effects are dependent on GPR55 activation, because they are abolished by pretreatment with ML-193 [N-(4-(N-(3,4-dimethylisoxazol-5-yl)sulfamoyl)-phenyl)-6,8-dimethyl-2-(pyridin-2-yl)quinoline-4-carboxamide], a selective GPR55 antagonist. Thus, we provide the first pharmacological evidence that GPR55 activation at central levels is pronociceptive, suggesting that interfering with GPR55 signaling in the PAG may promote analgesia.
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.).
authors.forename: Elena
authors.initials: E
authors.lastname: Deliu
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.).
authors.forename: Margaret
authors.initials: M
authors.lastname: Sperow
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.).
authors.forename: Linda
authors.initials: L
authors.lastname: Console-Bram
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.).
authors.forename: Rhonda L
authors.initials: RL
authors.lastname: Carter
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.).
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.).
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kalamarides
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.).
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Kirby
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.).
authors.forename: G Cristina
authors.initials: GC
authors.lastname: Brailoiu
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.).
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.).
authors.forename: Khalid
authors.initials: K
authors.lastname: Benamar
authors.affiliation: Center for Substance Abuse Research (E.D., M.S., L.C.-B., D.J.K., L.G.K., E.B., K.B., M.E.A.), Department of Anatomy and Cell Biology (L.G.K., M.E.A.), Center for Translational Medicine and Department of Pharmacology (R.L.C., D.G.T.), Temple University School of Medicine, Philadelphia, Pennslyvania; and Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, Philadelphia, Pennsylvania (G.C.B.) mabood@temple.edu.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Abood
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000502:physiology; D058748:Pain Perception; D010487:Periaqueductal Gray / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000235:genetics* / Q000378:metabolism*
chemical_list: C526692:GPR55 protein, mouse; D008246:Lysophospholipids; D043882:Receptors, Cannabinoid; C025449:lysophosphatidylinositol; D002118:Calcium