title: Morphine induces hyperalgesia without involvement of μ-opioid receptor or morphine-3-glucuronide.
abstract: Opioid-induced hyperalgesia (OIH) is a paradoxical increase in pain perception that may manifest during opioid treatment. For morphine, the metabolite morphine-3-glucuronide (M3G) is commonly believed to underlie this phenomenon. Here, in three separate studies, we empirically assess the role of M3G in morphine-induced hyperalgesia. In the first study, CD-1 mice injected with morphine (15 mg/kg subcutaneously) after pretreatment with the opioid receptor antagonist naltrexone (NTX) (15 mg/kg) showed tail withdrawal latency reductions indicative of hyperalgesia (2.5 ± 0.1 s at t = 30 min, P < 0.001 versus baseline). In these mice, the morphine/M3G concentration ratios versus effect showed a negative correlation (r(p) = -0.65, P < 0.001), indicating that higher morphine relative to M3G concentrations are associated with increased OIH. In the second study, similar hyperalgesic responses were observed in mice lacking the multidrug resistance protein 3 (MRP3) transporter protein (Mrp3(-/-) mice) in the liver and their wild-type controls (FVB mice; latency reductions: 3.1 ± 0.2 s at t = 30 min, P < 0.001 versus within-strain baseline). In the final study, the pharmacokinetics of morphine and M3G were measured in Mrp3(-/-) and FVB mice. Mrp3(-/-) mice displayed a significantly reduced capacity to export M3G into the systemic circulation, with plasma M3G concentrations just 7% of those observed in FVB controls. The data confirm previous literature that morphine causes hyperalgesia in the absence of opioid receptor activation but also indicate that this hyperalgesia may occur without a significant contribution of hepatic M3G. The relevance of these data to humans has yet to be demonstrated.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Swartjes
authors.forename: René A G
authors.initials: RA
authors.lastname: Mooren
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Waxman
authors.forename: Caroline
authors.initials: C
authors.lastname: Arout
authors.forename: Koen
authors.initials: K
authors.lastname: van de Wetering
authors.forename: Jan
authors.initials: J
authors.lastname: den Hartigh
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kest
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000818:Animals; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D009271:Naltrexone / Q000494:pharmacology; D011930:Reaction Time; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D009022:Morphine Derivatives; D017450:Receptors, Opioid, mu; D009271:Naltrexone; D009020:Morphine; C018108:morphine-3-glucuronide