TY - JOUR T1 - In vivo Activity of Norhydrocodone: An Active Metabolite of Hydrocodone JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.113.207548 SP - jpet.113.207548 AU - Dipesh M. Navani AU - Byron C. Yoburn Y1 - 2013/01/01 UR - http://jpet.aspetjournals.org/content/early/2013/08/30/jpet.113.207548.abstract N2 - Hydrocodone is primarily metabolized to hydromorphone and norhydrocodone. Although hydromorphone is a known active metabolite of hydrocodone, the in vivo activity of norhydrocodone is not well-documented. In the current study, the pharmacodynamics of norhydrocodone were evaluated and compared to hydrocodone and hydromorphone. Binding studies established that norhydrocodone, similar to hydrocodone and hydromorphone is a μ-selective opioid ligand. In vivo analgesia (tailflick) studies demonstrated that, following subcutaneous (SC), intrathecal (IT) and intracerebroventricular (ICV) administration, norhydrocodone produced analgesia. Following SC administration, norhydrocodone was ≈ 70-fold less potent and hydromorphone was ≈ 5.4-fold more potent than hydrocodone in producing analgesia. Following IT administration, norhydrocodone produced a shallow analgesia dose-response curve and maximal effect of 15-45%, while hydrocodone and hydromorphone produced dose-dependent analgesia. IT Hydromorphone was ≈ 174-fold more potent than IT hydrocodone. Following ICV administration, norhydrocodone had similar potency to hydrocodone in producing analgesia, while hydromorphone was ≈ 96-fold more potent than hydrocodone. Analgesia induced by the three drugs following SC, IT and ICV administration was antagonized by SC naltrexone, confirming that it is opioid receptor-mediated. SC norhydrocodone-induced analgesia was completely blocked by ICV naltrexone, indicating that norhydrocodone-induced analgesia is likely a supraspinal effect. Seizure activity was observed following IT administration of all three drugs. Norhydrocodone and hydromorphone were ≈ 3.7-4.6-fold more potent than hydrocodone in inducing seizure activity. Naltrexone did not antagonize opioid-induced seizure activity, suggesting seizures were non-opioid receptor-mediated. Taken together, norhydrocodone is an active metabolite of hydrocodone and may contribute to therapeutic and toxic effects following hydrocodone administration. ER -