Neuropharmacology and Analgesia Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice Ana Campillo, David Cabañero, Asunción Romero, Paula García-Nogales, Margarita María Puig ⁎ 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 abstract article info Article history: Received 12 November 2010 Received in revised form 7 January 2011 Accepted 25 January 2011 Available online 4 February 2011 Keywords: Dynorphin Kappa opioid receptor Latent pain sensitization Opioid Postoperative pain Remifentanil 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 (80 μg/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 (1 mg/kg), (+)-naloxone (1 mg/kg), naloxone-methiodide (3 mg/kg), or nor- binaltorphimine (5 mg/kg). Another group received subcutaneous MK-801 (0.15 mg/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 5 months 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. © 2011 Elsevier B.V. All rights reserved. 1. Introduction In a mouse model of post-surgical pain we have previously shown that the intraoperative administration of remifentanil enhances and extends postoperative pain sensitization (Cabañero et al., 2009a,b; Campillo et al., 2010; Célérier et al., 2006). It has also been reported that animals previously injured or exposed to opioids develop long- lasting pain vulnerability shown by increased susceptibility to develop hyperalgesia in response to new stimuli or opioid adminis- tration (Cabañero et al., 2009a; Rivat et al., 2002, 2007). This phenomenon is known as latent pain sensitization (Rivat et al., 2007) and may reflect the transition from acute to chronic pain. In animals exposed to pain or opioids, latent pain sensitization can be evidenced by the naloxone test (Célérier et al., 2001; Kim et al., 1990; Laulin et al., 2002; Li et al., 2001; Richebe et al., 2005), in which the abrupt blockage of the opioid receptors precipitates hyperalgesia. This response has been tentatively explained by an increase in endogenous opioid peptides and/or increased signaling activity at the opioid receptors (Célérier et al., 2001). However, the specific type of endogenous opioids and/or the opioid receptors implicated remain unclear. In addition, N-methyl-D-aspartate (NMDA) antagonists prevent naloxone-precipitated hyperalgesia in rats previously exposed to opioids (Laulin et al., 2002; Richebe et al., 2005). Although the NMDA receptor system seems to have an important role in latent pain sensitization, the series of events leading to its activation after exposure to opioids is unknown. It has been proposed that exposure to opioids up-regulates spinal dynorphin, that in turn would induce the release of excitatory transmitters from primary afferents (Gardell et al., 2002a,b; Vanderah et al., 2001). Dynorphin is an endogenous opioid with antinociceptive (binding to kappa opioid receptors), and pronociceptive effects, possibly acting on NMDA and/or bradykinin European Journal of Pharmacology 657 (2011) 89–96 ⁎ Corresponding author at: Department of Anesthesiology, Hospital del Mar, Passeig Marítim 25–29, E-08003 Barcelona, Spain. Tel.: +34 93 2483527; fax: +34 93 2483254. E-mail addresses: apillu@gmail.com (A. Campillo), davidmail@graffiti.net (D. Cabañero), mromero@imim.es (A. Romero), paulagn4@googlemail.com (P. García-Nogales), MPuigR@hospitaldelmar.cat (M.M. Puig). 0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.01.059 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar