The proposed experiments are designed to lead to a better understanding of the neural circuitry that underlies physical dependence on acute and chronic opioids. Opioid physical dependence is defined by the appearance of a variety of physiological and psychological symptoms that occur when an opioid agonist is terminated or an antagonist administered. This opioid abstinence syndrome includes spontaneous pain as well as increases in autonomic outflow that produce tachycardia, tachypnea and an elevated blood pressure. The proposed experiments will examine the neural basis for the nociceptive facilitation and the sympathoexcitation that occur during opioid withdrawal. The rostral ventromedial medulla (RVM), the ventrolateral medulla (VLM), the pontine locus coeruleus (LC) and the midbrain periaqueductal gray (PAG) all contain opioid sensitive neurons and have been implicated in one or more of the components of opioid physical dependence. The RVM is a nociceptive modulatory region that contains a population of cells that facilitate nociceptive transmission during opioid withdrawal. RVM neurons project to both the spinal dorsal horn and the VLM. The VLM, an autonomic and somatic modulatory region, projects to the spinal dorsal and intermediate horns. The VLM is a major source of afferents to the LC and is required for the activation of LC neurons during opioid withdrawal. The LC, a noradrenergic nucleus important in the control of overall arousal and vigilance, has been implicated in the production of most components of the opioid abstinence syndrome. Regional glucose utilisation is elevated in both the LC and the PAG during naloxone- precipitated withdrawal from chronic opioids. PAG stimulation modulates somatic and autonomic activity and contains cells that project to both the VLM and RVM. The brainstem pathways that produce the nociceptive facilitation and autonomic responses of the opioid abstinence syndrome will be traced by blocking synaptic transmission in selected brain regions during naloxone precipitated withdrawal from systemic opioids. The contribution of the RVM, VLM, and LC to the nociceptive and cardiopulmonary components of chronic and acute opioid physical dependence will be described and compared. To further define the site or sites of opioid action necessary for nociceptive facilitation and autonomic arousal during physical dependence, naloxone will be administred following the microinjection of a low, medium and high dose of morphine into the opioid-sensitive RVM, VLM and LC. Electrophysiological experiments will detail the physiological characteristics of single VLM and PAG neurons during acute and chronic opioid physical dependence. A high and a low dose of morphine will be tested in both the acute and chronic experiments. Furthermore, the afferents responsible for the activity of VLM neurons will be examined by inactivating RVM and PAG neurons during opioid withdrawal. This experiment will also be performed in animals treated both acutely and chronically with either a high or low dose of morphine.
