Pain perception is strongly inhibited by two descending systems. One system depends on opioid receptors. The second system, the opioid-independent (OI) system is independent of opioid receptors. The cellular basis and the pharmacology of the OI pain inhibitory system are not well understood. This system can be activated by severe stress or by injection of neurotensin (NT) into the periaqueductal gray (PAG). In addition, we have shown that NT-mediated analgesia can be blocked by depletion of spinal norepinephrine. Our recent studies have shown that OI analgesia (OIA) produced by stress of swimming rats in cold water can be blocked by injection of an NT antagonist (SR48692) or by blocking adrenergic receptors. Together these findings indicate that the neurotensinergic (NT-ergic) system of the PAG, acting through an adrenergic pathway, is crucial for the function of OIA. The goals of this study are to test the hypotheses that (1) OIA is produced by activation of forebrain (FB) NT-ergic neurons that project to the PAG, and (2) activation of PAG regions then activates pontine and medullary noradrenergic neurons that have direct projections to the spinal cord dorsal horn. To test these hypotheses (1) We will use in situ hybridization to identify the brain regions that show increase in expression of NT mRNA and tyrosine hydroxylase mRNA. (2) By using multiple-labeling procedures we will identify the sources of NT-ergic neurons that project to the PAG regions where injection of NT produces analgesia. (3) Using the same procedures, we will also identify the anatomical properties of the efferents of these PAG regions to the pontine and medullary sites that are involved in pain inhibition. (4) We will use behavioral testing procedures to determine the function role of the NT-ergic afferents to the PAG in the production of OIA. (5) We will use behavioral testing procedures to determine the effects of lesions of the noradrenergic nuclei in NT-mediated OIA. (5) Because PAG plays a significant role in cardiovascular regulation and these systems are involved in the response to stress, we will examine the role of NT-ergic afferents to the PAG in cardiovascular regulation. These studies will significantly increase our understanding of the OIA and will be of value in understanding pain processing by the brain. Since OIA does not have the problems that are associated with opioids, these studies have the potential for improving pain management and control.
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