Chronic use of opioids results in tolerance and physical dependence. Both processes are due to adaptive changes in neurons resulting from continued exposure to agonists. However, the neuronal mechanisms underlying physical dependence, characterized by a rebound excitation on withdrawal of agonists, remain poorly understood. Several brain regions including the periaqueductal gray (PAG) are thought to play a pivotal role in expression of physical dependence on opioid drugs. The goal of the proposed studies is to determine the ionic and second messenger mechanisms causing physical dependence in single PAG neurons. In particular, we propose to: Further characterise opioid modulated ionic conductances, particularly voltage activated potassium and nonselective cation conductances in mouse PAG neurons to inform studies of adaptations following chronic morphine treatment. Characterise the processes of tolerance to opioid agonists for the various ionic conductances modulated by mu opioid receptors in mouse PAG neurons. Characterise the ionic currents underlying excitation of mouse PAG neurons during opioid withdrawal. Identify key adaptations to second messenger systems underlying the changes found in Aim 3) using modulators of second messenger systems and genetically modified mice. Characterise the changes in GABAergic and glutamatergic synaptic transmission that occur during withdrawal excitation in mouse PAG. Identify key adaptations to second messenger systems underlying the changes found in Aim 5) using modulators of second messenger systems and genetically modified mice.
