The long-term goals of this project are to understand how endogenous opioid peptides and their receptors contribute to the regulation of stress-related behavior and nociception. Neural systems exist within the brain and spinal cord that can, when activated, modulate the transmission of information about noxious stimuli. Recent studies we have conducted indicate that the amygdaloid complex appears to be a critical forebrain region involved in the activation of these systems in response to environmental stress. We have proposed that efferent projections from the central nucleus of the amygdala to the ventrolateral periaqueductal gray (PA~)are critical for certain forms of stress-related hypoalgesia and cardiovascular alterations in the rat and have developed a model system using a spinally-mediated nociceptive reflex to test this idea. This proposal describes a series of experiments that are focused on understanding the functions of endogenous opioid peptides in the amygdala and PAG. In all experiments we will simultaneously measure arterial blood pressure and heart rate along with nociception while microinjecting selective opioid agonists and antagonists into these two brain structures. In the first set of studies, we will use a barbiturate- anesthetized rat preparation to address opioid modulation of the radiant heat tail flick reflex. We have recently shown that microinjection of mu, but not delta or kappa, opioid receptor agonists into the anterior basolateral nucleus of the amygdala in anesthetized rats will result in a dramatic inhibition of this nociceptive reflex. We will explore the neuropharmacology of this effect within the amygdala in greater detail and determine if chemical stimulation of the amygdala in this preparation causes the release of opioid peptides in the PAG. The second set of experiments will determine if opioid microinjection into the amygdala results in a dose-related inhibition of nociception in awake animals comparing both tail flick and the formalin test as behavioral assays. The final set of experiments will provide important information about endogenous opioid release in the amygdala and PAG during stress-induced hypoalgesia. Using a highly reliable Pavlovian conditioning procedure to produce stimulus-dependent opioid-mediated inhibition of the tail flick response, we will be able to directly compare patterns of endogenous opioid peptide involvement in nociceptive inhibition and cardiovascular alterations in awake and in anesthetized rats. The knowledge gained from these studies should have an appreciable impact on our understanding of endogenous opioid mechanisms of antinociception and thus may eventually aid the development of safer and more effective analgesic compounds for clinical use.
Showing the most recent 10 out of 11 publications
