title: Signaling pathway of morphine induced acute thermal hyperalgesia in mice.
abstract: Systemic administration of morphine induced a hyperalgesic response in the hot plate test, at an extremely low dose (1-10 microg/kg). We have examined in vivo whether morphine, at an extremely low dose, induces acute central hypernociception following activation of the opioid receptor-mediated PLC/PKC inositol-lipid signaling pathway. The PLC inhibitor U73122 and the PKC blocker, calphostin C, dose dependently prevented the thermal hypernociception induced by morphine. This effect was also prevented by pretreatment with aODN against PLCbeta3 at 2 nmol/mouse and PKCgamma at 2-3 nmol/mouse. Low dose morphine hyperalgesia was dose dependently reversed by selective NMDA antagonist MK801 and ketamine. This study demonstrates the presence of a nociceptive PLCbeta3/PKCgamma/NMDA pathway stimulated by low concentrations of morphine, through muOR1 receptor, in mouse brain. This signaling pathway appears to play an opposing role in morphine analgesia. When mice were treated with a morphine analgesic dose (7 mg/kg), the downregulation of PLCbeta3 or PKCgamma at the same aODN doses used for the prevention of the hyperalgesic effect induced, respectively, a 46% and 67% potentiation in analgesic response. Experimental and clinical studies suggest that opioid may activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. The clinical management of pain by morphine may be revisited in light of the identification of the signaling molecules of the hyperalgesic pathway.
authors.affiliation: Department of Clinical and Preclinical Pharmacology, University of Florence, Florence, Italy Neuroscience Research Institute, State University of New York, NY, USA Department of Biomedical Sciences, University of Siena, Siena, Italy Department of Neuroscience, University of Siena, Siena, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Galeotti
authors.forename: George B
authors.initials: GB
authors.lastname: Stefano
authors.forename: Massimo
authors.initials: M
authors.lastname: Guarna
authors.forename: Enrica
authors.initials: E
authors.lastname: Bianchi
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
mesh_terms: D000698:Analgesia; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D015151:Immunoblotting; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D054799:Phospholipase C beta; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C011439:1,2-diacylglycerol; D000701:Analgesics, Opioid; D004075:Diglycerides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007527:Isoenzymes; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine; D000242:Cyclic AMP; C087857:protein kinase C gamma; D011493:Protein Kinase C; D010738:Type C Phospholipases; D054799:Phospholipase C beta