Mechanisms of opioid actions on neurons of the locus coeruleus

The locus coeruleus (LC) has provided a useful model for pioneering studies of the mechanisms underlying the acute and chronic actions of opioid drugs. Acutely, opioids inhibit the electrical activity of single neurons in the rat and guinea pig LC. Inhibition is due to a membrane hyperpolarisation. In these cells, opioids act on mu-receptors to increase the opening of inwardly rectifying potassium channels, thus leading to hyperpolarisation. The mu-receptors are coupled to potassium channels via G-proteins which are sensitive to inactivation by pertussis toxin. This coupling process is quite direct, in that it does not involve freely diffusible intracellular second messengers. Agonists specific for other receptors, such as alpha 2- and somatostatin-receptors, are capable of opening the same population of potassium channels on LC neurons. Following chronic treatment of animals with morphine, a specific deficit develops in the ability of mu-receptors to open potassium channels, producing reduced sensitivity of LC neurons to inhibition by opioids.