title: A murine model of opioid-induced hyperalgesia.
abstract: Controversies surround the possible long-term physiological and psychological consequences of opioid use. Analgesic tolerance and addiction are commonly at the center of these controversies, but other concerns exist as well. A growing body of evidence suggests that hyperalgesia caused by the chronic administration of opioids can occur in laboratory animals and in humans. In these studies we describe a murine model of opioid-induced hyperalgesia (OIH). After the treatment of mice for 6 days with implanted morphine pellets followed by their removal, both thermal hyperalgesia and mechanical allodynia were documented. Additional experiments demonstrated that prior morphine treatment also increased formalin-induced licking behavior. These effects were intensified by intermittent abstinence accomplished through administration of naloxone during morphine treatment. Experiments designed to determine if the mu-opioid receptor mediated OLH in our model revealed that the relatively-selective mu-opioid receptor agonist fentanyl induced the thermal hyperalgesia and mechanical allodynia characteristic of OIH when administered in intermittent boluses over 6 days. In complimentary experiments we found that CXBK mice which have reduced mu-opioid receptor binding displayed no significant OIH after morphine treatment. Finally, we explored the pharmacological sensitivities of OIH. We found that the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) and the heme oxygenase (HO) inhibitor tin protoporphyrin (Sn-P) dose-dependently reduced OIH in this model while the NSAID indomethacin had no effect. Thus we have characterized a murine model of OIH which will be useful in the pursuit of the molecular mechanisms underlying this phenomenon.
authors.affiliation: Veterans Affairs Palo Alto Health Care System and Stanford University Department of Anesthesiology, 3801 Miranda Ave., Palo Alto, CA 94304, USA.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: M S
authors.initials: MS
authors.lastname: Angst
authors.forename: J D
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005283:Fentanyl / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced*; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010147:Pain Measurement; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics*
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D005283:Fentanyl