Chronic pain and alcohol consumption are strongly associated, but the directionality of this relationship remains unclear, reflecting their complex interaction. Epidemiological studies indicate that individuals with alcohol use disorder (AUD) are at increased risk of developing pain symptoms (Hung et al., 2021). Chronic alcohol use is associated with pain exacerbation and heightened pain during abstinence (Zale et al., 2015; Ditre et al., 2019; Bergeson et al., 2016a, Bergeson et al., 2016b). This relationship is bidirectional; for example, the prevalence of AUD increases following bariatric surgery (King et al., 2012). Conversely, many patients with chronic pain report using alcohol for pain relief (Riley and King, 2009; Imtiaz et al., 2018; Alford et al., 2016), particularly heavy drinkers (Brennan et al., 2005). Alcohol withdrawal-associated hyperalgesia may act as a negative reinforcer, escalating drinking and relapse risk (Powers et al., 2019; Egli et al., 2012; Zale et al., 2015). Thus, chronic pain and alcohol use likely drive a positive feedback loop that exacerbates both conditions over time (Ditre et al., 2019; Edwards et al., 2020). It is not very clear however to what extent the relationship between alcohol use and pain is moderated by biological sex. Clinical and preclinical data both indicate that sex may play a role in determining the pain–alcohol relationship. For example, men are more likely to engage in heavy drinking, whereas women more often abstain or discontinue (Wilsnack et al., 2009); however, women progress more rapidly to AUD and show greater alcohol-induced neurotoxicity (Boissoneault et al., 2019; Wilsnack et al., 2009; Alfonso-Loeches et al., 2013).

Preclinical studies similarly reveal sex-dependent alcohol effects; for instance, alcohol-induced antinociception was more potent in males mice compared to females mice (White et al., 2023). We recently reported that laparotomy surgery increased alcohol intake and preference in male but not female mice in the two-bottle choice (2BC) assay (Ghani et al., 2024). Similarly, male mice with osteoarthritis (Butler et al., 2017) or partial sciatic nerve ligation (González-Sepúlveda et al., 2015) also displayed increased alcohol intake. However, findings from intraplantar injection of Complete Freund's Adjuvant (CFA) have been mixed. For example, CFA-induced inflammatory pain increased alcohol reinstatement in female rats (Lorente et al., 2021), had no effect in male rats (Adrienne McGinn et al., 2020), but increased daily intake in male mice (Yu et al., 2019). Altogether, these studies suggest possible species-, strain- or pain modality-dependent interactions. In addition, these mixed findings also highlight the importance of examining sex as a biological variable in chronic pain–alcohol interactions.

It is also unclear how pain modality and type can affect these interactions. Preclinical studies can provide critical insights for examining how experimentally induced different types of pain can influence voluntary alcohol consumption.

Beyond sex differences and pain modality, specific neurobiological systems seem to mediate pain–alcohol interactions. One strong candidate is the dynorphin/kappa opioid receptor (Dyn/KOR) system, which modulates alcohol's pharmacological effects and intake (Karkhanis et al., 2016; Rose et al., 2016). Chronic pain recruits Dyn/KOR signaling in mesolimbic circuits, reducing dopamine release and promoting negative affective states (Massaly et al., 2019; Tejeda and Bonci, 2019; Walker and Koob, 2008). KOR activation contributes to withdrawal-related dysphoria and escalated drinking, while KOR antagonism reduces excessive intake (Walker and Koob, 2008; Lorente et al., 2021). We therefore hypothesized that the selective KOR antagonist nor-binaltorphimine dihydrochloride (nor-BNI) would normalize pain-facilitated ethanol intake in mice.

Accordingly, we investigated how chronic inflammatory and neuropathic pain affect ethanol drinking in C57BL/6J mice. We measured alcohol intake in both the CFA inflammatory pain model and the chemotherapy-induced peripheral neuropathy (CIPN) model in males and females. We further tested whether KOR signaling mediates CFA-evoked changes in alcohol intake using the selective KOR antagonist, nor-BNI.