Finally, in addition to evidence for KOR involvement in dysphoria/negative affect related to ethanol withdrawal, two preclinical studies have examined effects of KOR antagonism on physical symptoms of withdrawal following ethanol vapor exposure. In rats, nor-BNI had no effect on acute or protracted withdrawal symptoms including ventromedial distal limb flexion response, tail rigidity, and gait abnormalities (Kissler and Walker, 2016). However, another report found that nor-BNI increased withdrawal seizure severity (assessed by measuring handling-induced convulsions) in a seizure-resistant inbred mouse strain (Beadles-Bohling and Wiren, 2006). These findings were somewhat corroborated by another report that compared handling-induced convulsions during withdrawal from acute ethanol (4 g/kg, po) in prodynorphin knockout and wild-type mice (Femenia and Manzanares, 2012). Additional research is needed to further characterize these effects in preclinical models, especially if KOR antagonists are to be considered as potential therapeutics for alcohol use disorder.
