The Role of Glutamate in Physical Dependence on Opioids

The present review will evaluate the interactions between κ-opioid receptors and glutamate within the locus coeruleus (LC) during the development of opioid dependence and on expression of withdrawal from dependence on opioids. Hyperactivity of noradrenergic neurons in the LC has been proposed to play a critical role in the physiological and behavioral responses that comprise opioid withdrawal. Several studies indicate that the excitatory amino acid system, in particular, glutamate and its receptors, participate in both the withdrawal-associated increase in LC neuronal activity and the expression of opioid withdrawal behaviors. Most studies on opioid dependence have focused on the prototypical opioid morphine, which produces its physical dependence through agonist actions at the μ-opioid receptor. Butorphanol (Stadol®), which exhibits a markedly different profile of opioid receptor activity than does morphine, produces its physical dependence primarily through actions at the κ-opioid receptor. Studies from our laboratories using a rodent model in which butorphanol administration induces dependence indicate further that the κ-opioid receptor is an important regulator of glutamate release within the LC. Glutamate exerts actions within the LC that mediate expression of behavioral symptoms of butorphanol withdrawal.