Downregulation of M-channels in lateral habenula mediates hyperalgesia during alcohol withdrawal in rats

Hyperalgesia often occurs in alcoholics, especially during abstinence, yet the underlying mechanisms remain elusive. The lateral habenula (LHb) has been implicated in the pathophysiology of pain and alcohol use disorders. Suppression of m-type potassium channels (M-channels) has been found to contribute to the hyperactivity of LHb neurons of rats withdrawn from chronic alcohol administration. Here, we provided evidence that LHb M-channels may contribute to hyperalgesia. Compared to alcohol naive counterparts, in male Long-Evans rats at 24-hours withdrawal from alcohol administration under the intermittent access paradigm for eight weeks, hyperalgesia was evident (as measured by paw withdrawal latencies in the Hargreaves Test), which was accompanied with higher basal activities of LHb neurons in brain slices, and lower M-channel protein expression. Inhibition of LHb neurons by chemogenetics, or pharmacological activation of M-channels, as well as overexpression of M-channels' subunit KCNQ3, relieved hyperalgesia and decreased relapse-like alcohol consumption. In contrast, chemogenetic activation of LHb neurons induced hyperalgesia in alcohol-naive rats. These data reveal a central role for the LHb in hyperalgesia during alcohol withdrawal, which may be due in part to the suppression of M-channels and, thus, highlights M-channels in the LHb as a potential therapeutic target for hyperalgesia in alcoholics.