The calcium channel agonist (±)-BAY-K-8644 attenuates the ability of gabapentinoids to increase the potency of fentanyl and heroin and decrease the potency of cocaine and d-methamphetamine to elicit discriminative stimulus effects in rats

During the opioid epidemic there has been a significant increase in the number of prescriptions for gabapentinoids (gabapentin and pregabalin), which block the α2δ-subunit of voltage-gated calcium channels (VGCCs). In rats, gabapentinoids enhance the potency of the mu opioid receptor (MOR) agonists fentanyl and heroin and decrease the potency of the stimulant drugs cocaine and d-methamphetamine to elicit discriminative stimulus effects. Moreover, (±)-BAY-K-8644, a dihydropyridine-type agonist at the α1-subunit of VGCCs (α1-VGCCs), prevents the antiallodynic effects of gabapentin in rats. The mechanism(s) of interaction between gabapentinoids and MOR agonists and between gabapentinoids and stimulant drugs is/are unclear. This study tested the following hypotheses: (1) the dihydropyridine-type α1-VGCC blocker nimodipine increases the potency of MOR agonists to elicit discriminative stimulus effects; and (2) (±)-BAY-K-8644 attenuates the ability of gabapentinoids and nimodipine to increase the potency of MOR agonists to elicit discriminative stimulus effects. In rats trained to discriminate fentanyl (0.0032 mg/kg) or cocaine (3.2 mg/kg) from saline, neither (±)-BAY-K-8644 nor nimodipine elicited significant fentanyl- or cocaine-appropriate responding. (±)-BAY-K-8644 did not significantly alter discrimination dose-effect functions of MOR agonists or stimulant drugs whereas nimodipine dose-dependently shifted the MOR agonist discrimination dose-effect functions to the left and the stimulant drug discrimination dose-effect functions to the right. (±)-BAY-K-8644 dose-dependently attenuated the ability of nimodipine and gabapentinoids to increase the potency of MOR agonists and decrease the potency of stimulant drugs to elicit discriminative stimulus effects. These results suggest that gabapentinoids alter the potency of MOR agonists and stimulant drugs to elicit discriminative stimulus effects via blockade of α1-VGCCs. SIGNIFICANCE STATEMENT: Prescriptions for gabapentinoids (gabapentin and pregabalin) increased significantly during the opioid epidemic. Using (±)-BAY-K-8644, a dihydropyridine-type agonist at the α1-subunit of the voltage-gated calcium channel (α1-VGCC), this study reports that in male and female rats, gabapentinoids increase the potency of fentanyl and heroin and decrease the potency of cocaine and d-methamphetamine to elicit discriminative stimulus effects via blockade of dihydropyridine-binding sites on α1-VGCC. These results suggest that actions of drugs at α1-VGCCs contribute to the opioid epidemic and opioid/stimulant co-use.