The opiate analgesic drug morphine (MOR) has been shown to relieve pain by mechanisms that include the release of neuronal histamine (HA) and the subsequent activation of HA receptors in the periaqueductal grey (PAG). HA is known to function as a neuromodulator substance in the central nervous system. The proposed studies will characterize the sites and mechanisms by which HA relieves pain, and search for novel, pain-relieving medications based on these mechanisms. The experiments will use the techniques of in vivo microdialysis, intracerebral injections, and nociceptive testing in rats. The following studies will be performed: 1) MOR increases the release of neuronal HA in the PAG. To determine the mechanisms of this response, the effects of selective opiate receptor agonists and antagonists will be studied on the release of HA in the PAG in vivo. 2) HA injections into the PAG induce pain-relieving (i.e. analgesic) responses and, at higher doses, pain-enhancing (i.e. hyperalgesic) responses. To discover the pharmacological mechanisms underlying the HA-induced changes in nociceptive threshold, the effects of selective HD agonists and HA antagonists will be studied after intracerebral administration into the PAG. The unique HA-like compound SKF92374 will also be studied, since this agent appears to induce analgesic, but not hyperalgesic responses by a previously undiscovered mechanism. 3) HA and MOR interact to produce synergistic analgesic responses. To characterize the nature of these interactions, quantitative antinociceptive studies will be performed with combinations of various doses of HA and MOR. In addition, the effects of antagonists selective for sub-types of opiate receptors and HA receptors will be studied on these responses in the presence of these MOR-HA combinations. In addition to these studies of the PAG, pilot studies suggest that HA may also be an antinociceptive mediator in the raphe magnus (RM, another brain stem structure known to be important in pain relief). To address this hypothesis, several of the experiments proposed above for the PAG will also be performed in the RM. These studies will clarify the mechanisms by which MOR relieves pain, enhance the understanding of histaminergic antinociceptive mechanisms, and may lead to the discovery of non-addicting, novel medications for the treatment of pain.
Showing the most recent 10 out of 74 publications
