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UBC Theses and Dissertations

Behavioural effects of novel clinical candidate drugs, l-tetrahydropalmatine (l-THP) and Z944, on morphine withdrawal-induced hyperalgesia Oleinichenko, Daria


Opioid use disorder (OUD) is a major contributor to drug-related deaths worldwide. Opioid use cessation causes severe withdrawal symptoms, including prominent hyperalgesia – a contributor to the negative reinforcement of drug taking. Effective pain control is an underappreciated aspect of managing opioid withdrawal, and its absence presents a significant barrier to successful opioid detoxification. Exploring analgesic interventions for withdrawal-induced hyperalgesia may reveal novel OUD therapies. This thesis describes a model of hyperalgesia in both acute and extended withdrawal in morphine-dependent animals and the effect of two clinical candidate analgesic drugs on withdrawal-induced hyperalgesia. l-Tetrahydropalmatine (l-THP) is a tetrahydroprotoberberine compound and active ingredient of a botanical formulation used in Vietnam for OUD treatment with preclinical efficacy in neuropathic pain models. Z944 is a selective T-type calcium channel antagonist undergoing clinical trials as an anticonvulsive and analgesic. To establish drug dependence modelling intermittent access during abuse scenarios, morphine (15 mg/kg, i.p.) was given once a day, 5 days/week and Von Frey tests were conducted 2-3 times a week ~23 h after morphine injection. Animals subjected to three weeks of morphine treatment experienced a ~30% reduction in pain tolerance. To model hyperalgesia during detoxification, animals entered abstinence after 3 weeks of morphine treatment and with Von Frey testing showing that hyperalgesia was persistent for 14 days before spontaneous recovery. Both l-THP (5 or 7.5 mg/kg, p.o.) and Z944 (10 mg/kg, p.o.) were effective at attenuating hyperalgesia during acute withdrawal. Seven-day treatment with l-THP (5 mg/kg) or Z944 (10 mg/kg) in morphine-dependent animals undergoing extended withdrawal resulted in a significant increase in paw retraction thresholds compared to controls and this effect persisted after the completion of treatment. Importantly, the improvement in pain tolerance remained after treatment completion, hastening pain tolerance recovery to baseline by 61% and 80% (l-THP and Z944, respectively). Neither candidate drug influenced mechanical sensitivity in morphine-naïve animals. Overall, these findings support the hypothesis that pain management during detoxification is necessary for improved treatment outcomes. l-THP and Z944, therefore, may be a valuable addition to the currently limited arsenal of opioid detoxification treatments.

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