PI's abstract): The long-term goals of this project are to gain understanding of the means by which the brainstem mediates some of the analgesic effects of opioids. In the present proposal we concentrate on the involvement of the periaqueductal gray matter. The periaqueductal gray matter is a key structure in mediation of opioid analgesia. However, the relationship between opioid receptors, GABAergic neurons, medullary projection neurons, endogenous opioids, and opioid responses is not clear. Thus we propose the following specific aims: To determine whether axon terminals (and in particular GABAergic terminals) immunoreactive for the cloned mu-opioid receptor (MOR1) are in synaptic contact with PAG neurons projecting to the rostral ventromedial medulla (PAG-RVM neurons). In addition, to determine whether neurons hyperpolarized by opioids in the PAG are GABAergic. To determine the cellular effects in the PAG of activation of delta-opioid receptors and determine the synaptic relationship of processes immunoreactive for the cloned delta-opioid receptor (DOR1) to physiologically and anatomically characterized PAG neurons. To determine the cellular distribution of MOR1-ir and DOR1-ir in PAG-RVM neurons. To determine whether neurons responsive to mu-opioid receptors are under the synaptic control of endogenous opioid circuits. To determine the origin of MOR1 and DOR1 immunoreactive processes in the PAG. Addressing these issues will increase our knowledge of the PAG circuitry associated with antinociception. Ultimately, it is hoped that they will suggest novel clinical strategies for inducing or augmenting analgesia.
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