A murine model of opioid-induced hyperalgesia.

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.