Research Project
2654374
It is well known that the CNS contains opiate and non-opiate circuitry that acts to inhibit pain via production of analgesia. This circuitry can be activated by aversive or stressful stimuli, or environmental cues that predict impending exposure to such stimulation. Our recent evidence suggests hyperalgesia mechanisms may increase pain sensitivity in a manner complementary to analgesia mechanism activity: 1)Just as analgesia can be activated by exposure to a stressful or aversive external stimulus, central hyperalgesia mechanisms can be activated by acute exposure to an aversive internal stimulus. An aversive internal state is produced through intraperitoneal (IP) injection of lithium chloride (LiCl) or lipopolysaccharides (Endotoxin), which induce a potent cutaneous hyperalgesia as measured by the tailflick test of pain sensitivity. 2) Just as animals can learn to become analgesic in response to environmental cues that predict impending stressful or aversive external stimulation (conditioned analgesia), animals can learn to activate central mechanisms to become hyperalgesic in response to cues that predict impending internal aversive stimulation (conditioned hyperalgesia). A cue for an impending internal aversive state (emesis) was established by repeatedly pairing a novel taste with IP LiCl (conditioned taste aversion). 3)Endogenous opiates are implicated in the mediation of both the acute and learned forms of this hyperalgesia, as systemic naltrexone reverses the effect. The possibility that environmental stressors, cues for such, or analgesic agents such as the opiates may result in the simultaneous activation of both pain inhibitory and pain facilitory mechanisms has clinical implications. An understanding of these hyperalgesia systems and how they might interact with pain inhibitory processes could lead to the development of novel approaches for the control of pain and treatment of addiction. The aim of this proposal is to investigate: 1)the endogenous mechanisms underlying these central hyperalgesia systems, and 2) the possible impact of hyperalgesia system activation on the pain inhibition or analgesic efficacy produced in conditioned analgesia and acute morphine analgesia paradigms. CNS pharmacology (intrathecal and intracerebroventricular microinjection studies), lesion (electrolytic and excitotoxic lesions of specific brain sites), and behavior studies will be conducted to address basic, well defined issues central to the understanding and characterization of the mechanisms of this newly discovered circuitry.
