Acute morphine hyperalgesia: A pharmacological and pharmacogenetic analysis

• Main Author: Waxman, Amanda R
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2012
• Subjects: Neurosciences; Pharmacology; Physiological psychology
• ISBN: 9781267684974; 1267684976

Opioids such as morphine remain the most efficacious and widely used analgesics for moderate to severe pain. However, the clinical use of these opioids is complicated by unwanted side effects, including a paradoxical increase in pain sensitivity (i.e. hyperalgesia). Previous studies have demonstrated that sustained delivery of these opioids causes hyperalgesia independent of opioid receptor activity or analgesia. Unknown, however, is if a single acute morphine bolus dose similarly induces hyperalgesia that is independent of opioid receptor activity or analgesia. The current studies aimed to characterize the pharmacological, physiological, and organismic variables that govern acute morphine hyperalgesia. Outbred CD-1 male mice, pretreated with the general opioid receptor antagonist, naltrexone (NTX), did not exhibit analgesia, but demonstrated hyperalgesia after systemic administration of morphine. Acute morphine injection caused significant decreases in withdrawal latencies on the tail-withdrawal test and significant increases of licking behavior on the formalin test, both indicative of hyperalgesia, in male CD-1 mice pretreated with NTX and in male mice lacking all three genes encoding the µ, κ, and δ opioid receptors. Additionally, male mice lacking the pronociceptive morphine metabolite, morphine-3β-glucuronide (M3G), also demonstrated acute morphine hyperalgesia. Therefore, acute morphine hyperalgesia was characterized as an active process that is independent of prior or concurrent opioid receptor activity, analgesia, and the morphine metabolite, M3G. Additionally, to assess whether spinal and/or supraspinal loci contribute to acute morphine hyperalgesia, mice were pretreated with NTX and then tested for nociception on the tail-flick test before and after receiving an acute morphine via the intrathecal (i.t.) or intracerebroventricular (i.c.v.) route. Acute i.t. and i.c.v. morphine injection both caused significant hyperalgesia in mice subject to concurrent opioid receptor blockade by NTX, indicating that supraspinal and spinal loci significantly contribute to acute morphine hyperalgesia. Since acute morphine hyperalgesia occurs independently of opioid receptor activity and morphine metabolites, the contribution of N-methyl-D-aspartate (NMDA) receptors in acute morphine hyperalgesia was investigated. Systemic administration of the NMDA receptor antagonist MK-801 completely abolished acute morphine-induced hyperalgesia in CD-1 male mice pretreated with NTX. Furthermore, the contribution of NMDA receptors at spinal and supraspinal loci was also studied in NTX-treated mice by assaying nociception before and after i.t. or i.c.v. MK-801 injection in mice treated with an acute systemic morphine. MK-801 injected supraspinally completely blocks hyperalgesia induced by systemic injection of morphine, whereas MK-801 injected into the spinal cord reduces, but does not completely block, hyperalgesia induced by systemic morphine injection. Lastly, since interindividual differences in magnitude of morphine withdrawal, analgesia, and tolerance have been previously demonstrated to be associated with genotypic variation, we also assessed whether the magnitude of acute morphine-induced hyperalgesia is similarly genotype-dependent. The data revealed marked genetic variation; whereas some strains displayed a 30-50% reduction in withdrawal latency, other strains failed to become hyperalgesic at any time during the 120-minute post-morphine testing interval. Our findings demonstrate that the magnitude of acute morphine hyperalgesia is genotype-dependent.