Pharmacologic hyperreactivity of kappa opioid receptors in periaqueductal gray matter during alcohol withdrawal syndrome in rats

Background Periaqueductal gray matter (PAG) is a brain region rich in kappa-opioid receptors (KOR). KOR in PAG mediates behavioral responses related to pain integration, and panic response, among others. Its participation in the addiction phenomena has been poorly studied. Hence, this preliminary study explored the pharmacological effects of KOR stimulation/blockade in dorsal-PAG (D-PAG) during alcohol withdrawal on anxiety-type behaviors and alcohol intake/preference. Methods Juvenile male Wistar rats were unexposed (A-naïve group) or exposed to alcohol for 5 weeks and then restricted (A-withdrawal group). Posteriorly, animals received intra D-PAG injections of vehicle (10% DMSO), salvinorin A (SAL-A; a selective KOR agonist), or 2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242; a highly selective KOR-antagonist). Subsequently, the defensive burying behavior (DBB) and alcohol intake/preference paradigms were evaluated. Results SAL-A markedly increased burying time, the height of bedding, and alcohol consumption/preference in A-withdrawal, while slightly increased the height of bedding in A-näive rats. PF-04455242 decreased both burying and immobility duration, whereas increases latency to burying, frequency of rearing, and the number of stretches attempts with no action on alcohol intake/preference in A-withdrawal rats. Conclusions In general, stimulation/blockade of KOR in A-withdrawal animals exert higher responses compared to A-naïve ones. SAL-A produced anxiety-like behaviors and increased alcohol consumption/preference, especially/solely in the alcohol-withdrawal condition, while PF-04455242 augmented exploration with no effects on alcohol intake/preference. Our findings suggest a possible pharmacologic hyperreactivity of the KOR in PAG during alcohol withdrawal.