The α3β4*nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies

Background and PurposeRecent data have indicated that 34* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal. Experimental ApproachesTo assess the role of 34* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence. Key ResultsBXD recombinant mouse lines demonstrated an increased expression of 3, 4 and 5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, 5 and 4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts. Moreover, selective 34* nACh receptor antagonists, -conotoxin AuIB and AT-1001, attenuated somatic signs of morphine withdrawal in a dose-related manner. In addition, two human datasets revealed a protective role for variants in the CHRNA3 gene, which codes for the 3 nACh receptor subunit, in opioid dependence and withdrawal. In contrast, we found that the 42* nACh receptor subtype is not involved in morphine somatic withdrawal signs. Conclusion and ImplicationsOverall, our findings suggest an important role for the 34* nACh receptor subtype in morphine physical dependence.