title: Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice.
abstract: The long-lasting post-surgical changes in nociceptive thresholds in mice, indicative of latent pain sensitization, were studied. The contribution of kappa opioid and N-methyl-d-aspartate (NMDA) receptors was assessed by the administration of nor-binaltorphimine or MK-801; dynorphin levels in the spinal cord were also determined. Animals underwent a plantar incision and/or a subcutaneous infusion of remifentanil (80μg/kg), and mechanical thresholds (von Frey) were evaluated at different times. On day 21, after complete recovery of mechanical thresholds and healing of the wound, one of the following drugs was administered subcutaneously: (-)-naloxone (1mg/kg), (+)-naloxone (1mg/kg), naloxone-methiodide (3mg/kg), or nor-binaltorphimine (5mg/kg). Another group received subcutaneous MK-801 (0.15mg/kg) before nor-binaltorphimine administration. Dynorphin on day 21 was determined in the spinal cord by immunoassay. In mice receiving remifentanil during surgery, the administration of (-)-naloxone or nor-binaltorphimine induced significant hyperalgesia even 5months after manipulation. Nociceptive thresholds remained unaltered after (+)-naloxone or naloxone-methiodide. On day 21 after manipulation, the administration of MK-801 prevented nor-binaltorphimine-induced hyperalgesia. No changes in dynorphin levels were observed before or after opioid antagonist administration. In conclusion, surgery produced latent pain sensitization evidenced by opioid antagonist-precipitated hyperalgesia. The effect was stereospecific, centrally originated, and mediated by kappa opioid receptors. The blockade of nor-binaltorphimine-induced hyperalgesia by MK-801, suggests that NMDA receptors are also involved. Our results show for the first time that surgery induces latent, long-lasting changes in the processing of nociceptive information that can be induced by non-nociceptive stimuli such as the administration of opioid antagonists.
authors.affiliation: Department of Anesthesiology, Pain Research Unit, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain, Passeig Marítim 25–29,E-08003 Barcelona, Spain. apillu@gmail.com
authors.forename: Ana
authors.initials: A
authors.lastname: Campillo
authors.forename: David
authors.initials: D
authors.lastname: Cabañero
authors.forename: Asunción
authors.initials: A
authors.lastname: Romero
authors.forename: Paula
authors.initials: P
authors.lastname: García-Nogales
authors.forename: Margarita María
authors.initials: MM
authors.lastname: Puig
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D004399:Dynorphins / Q000378:metabolism / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage* / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011183:Postoperative Complications / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D000077208:Remifentanil; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D009292:Narcotic Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017473:Receptors, Opioid, kappa; D009270:Naloxone; C051844:norbinaltorphimine; D009271:Naltrexone; D016291:Dizocilpine Maleate; D004399:Dynorphins; D000077208:Remifentanil