The long term goal is to investigate butorphanol tartrate (Stadol)-induced physical dependence. A potent non-scheduled opioid analgesic agent, butorphanol, has substantial physical dependence and abuse liability as noted by case studies of butorphanol of abuse, literature reports, and our own data. In such cases, the normal therapeutic dose may be exceeded, leading to ingestion of larger doses for a longer periods of time than recommended. The objectives of the proposed studies are to focus on the mechanism of physical dependence upon butorphanol. Specifically, based on our research efforts conducted during the current support, the roles of k-opioid receptors, release of the excitatory neurotransmitter, glutamate, and NMDA receptors in the locus coeruleus of butorphanol dependent rats will be the targets of our investigation.
Five specific aims will test the hypothesis that hyperexcitability of k-opioid receptors to opioid antagonists, induced by chronic exposure to butorphanol, results in exaggerated presynaptic release of glutamate and activation of postsynaptic glutamate receptors on noradrenergic neurons of the pontine locus coeruleus.
These specific aims are:
Aim 1 : Characterization of k-opioid receptors in the development of physical dependence upon butorphanol.
Aim 2 : Investigation of glutamatergic neurotransmission within the locus coeruleus during the precipitation of withdrawal from dependence upon butorphanol by discrete locus coeruleus administration of selective-opioid receptor antagonists.
Aim 3 : Examination of the neuroanatomical link between the n. paragigantocellularis and the locus coeruleus as the putative substrate mediating the effects of k-opioid receptor stimulation on locus coeruleus glutamate levels during precipitated withdrawal from dependence upon butorphanol.
Aim 4 : Characterization of the involvement of locus coeruleus glutamate receptor subtypes in the development of dependence upon and withdrawal from butorphanol.
Aim 5 : Correlation tests of the degree of alteration in k-opioid receptors with the degree of glutamate release, change in NMDA receptors, and behavioral responses in butorphanol dependence.