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Background Pain and substance use are frequently comorbid and have been shown to exert bidirectional effects. Self-medication of pain and distress via substance use is common and can be understood via negative reinforcement, ultimately strengthening the pathway between pain to substance use over time. As such, a testable model of the potentially modifiable candidate mechanisms that underlie the pain to substance use pathway is needed. Purpose This review proposes a testable model of pain as an antecedent to substance use to guide future research and inform clinical practice. Methods An integrative review of current evidence regarding pain, substance use, and associated risk factors (i.e., negative affect, pain-related attitudes, negative urgency, and substance use outcome expectancies) was conducted. Results The Catastrophizing, Anxiety, Negative Urgency, and Expectancy (CANUE) model highlights modifiable risk factors for self-medicating pain with substance use, including increased negative affect and maladaptive pain-related attitudes (i.e., pain catastrophizing, pain anxiety, and fear of pain), negative urgency, and substance-related outcome expectancies for pain relief and enhanced pain coping. Conclusions Targeted behavioral and psychological interventions that address these factors may facilitate more adaptive pain-coping responses, thereby reducing the impacts of pain on substance use. Systematic research is needed to evaluate the validity and clinical utility of this model.

Glutamate neurotransmission in the nucleus accumbens core (NAc) mediates ethanol consumption. Previous studies using non-contingent and voluntary alcohol administration in inbred rodents have reported increased basal extracellular glutamate levels in the NAc. Here, we assessed basal glutamate levels in the NAc following intermittent alcohol consumption in male Sprague-Dawley rats that had access to ethanol for 7 weeks on alternating days. We found increased basal NAc glutamate at 24 h withdrawal from ethanol and thus sought to identify the source of this glutamate. To do so, we employed a combination of microdialysis, slice electrophysiology and western blotting. Reverse dialysis of the voltage-gated sodium channel blocker tetrodotoxin did not affect glutamate levels in either group. Electrophysiological recordings in slices made after 24 h withdrawal revealed a decrease in spontaneous excitatory postsynaptic current (sEPSC) frequency relative to controls, with no change in sEPSC amplitude. No change in metabotropic glutamate receptor 2/3 (mGlu2/3) function was detected as bath application of the mGlu2/3 agonist LY379268 decreased spontaneous and miniature EPSC frequency in slices from both control and ethanol-consuming rats. The increase in basal glutamate was not associated with changes in the surface expression of GLT-1, however, a decrease in slope of the no-net-flux dialysis function was observed following ethanol consumption, indicating a potential decrease in glutamate reuptake. Taken together, these findings indicate that the increase in basal extracellular glutamate occurring after chronic ethanol consumption is not mediated by an increase in action potential-dependent glutamate release or a failure of mGlu2/3 autoreceptors to regulate such release.

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