| The mu opioid agonists, such as morphine, have been used for many years in the treatment of pain. There are two major supraspinal pain pathways. The ascending pathway carries pain signals from the periphery to the brain. Opioids directly inhibit the excitability of neurons in this pathway, resulting in reduced nociceptive information to the brain. The descending pathway starts in the brain and terminates at the spinal cord. Electrical stimulation or morphine microinjection directly into descending pain regions results in profound analgesia. The descending brain circuity includes the amygdala, the periaqueductal gray (PAG), and rostral ventralmedial medulla (RVM). Since postsynaptic mu opioid receptors are inhibitory in nature, mu opioids may indirectly excite, or disinhibit, neurons in these regions.; It is hypothesized that disinhibition is the primary mechanism used by opioids to stimulate regions in the descending pathway, ultimately resulting in analgesia. However, no studies have determined if mu opioids directly result in attenuation of the inhibitory input onto neurons that project from one descending region to another. Such a finding would show a functionally important role for disinhibition in opioid analgesia. The studies in this thesis utilized a combination of retrograde tracing and whole-cell patch clamp recordings in brain slices to test the hypothesis that stimulation of presynaptic mu opioid receptors attenuates the GABA inhibitory input to specific projection neurons within the descending pathway.; In spinally projecting RVM neurons, it was found that GABAergic input was attenuated by the mu opioid agonist in most neurons tested. Within the amygdala, two populations of neurons were examined. In PAG-projecting central nucleus of the amygdala (CeA) neurons, presynaptic mu opioid receptor stimulation resulted in a decrease in the GABAergic input in the majority of neurons examined, while glutamatergic input was largely unchanged. In the basolateral nucleus of the amygdala (BLA) neurons projecting to the CeA, the mu opioid agonist selectively decreased in GABAergic input. The results in the RVM and amygdala support a functionally important role for disinhibition as a means through which opioids influence other descending regions. |
