The attention of investigators interested in pain and analgesia has in recent years been increasingly directed toward understanding the mechanisms that underlie persistent pain states. The most intense effort has been focused upon elucidating the now well-documented plasticity of elements in nociceptive transmission pathways, including primary afferent nociceptors and ascending transmission circuits. By contrast, the possibility that changes in descending modulatory systems might contribute to persistent pain states has received comparatively little attention. Nevertheless, there is now mounting evidence pointing to an important role for a well-characterized brainstem pain modulating system in hyperalgesia and persistent pain. This system, with links in the midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), was once viewed as an """"""""analgesia system"""""""" activated by acute stress or pain or by opioid analgesic drugs to inhibit spinal nociceptive processing. It is now known to be more complex, with a potential for bi-directional control of nociception.
The aim of the present proposal is to analyze recruitment of this brainstem pain modulating system by interleukin-1beta (IL-1beta), a pro-inflammatory cytokine that orchestrates immune and neural responses to injury and infection. The applicants propose to use a combination of behavioral pharmacology and single cell recording methods to characterize the effects of IL-1beta on nociceptive responding, and to identify the central circuitry mediating these effects. They have found that administration of IL-1beta evokes a biphasic alteration in nociceptive responding, with a period of hyperalgesia followed by a later phase of hypoalgesia. They will therefore determine the time course of changes in nociceptive responding following systemic and intracerebroventricular administration of IL-1beta in both awake and isoflurane-anesthetized rats, and identify potential roles of prostanoids, NMDA, endogenous opioids or corticotropin releasing factor. Using a microinjection mapping technique, the investigators will test the hypothesis that IL-1beta acts directly within the hypothalamus and within RVM. They will further test the role of specific cell populations within the RVM using lesion and electrophysiological approaches. The role of brainstem pain modulating systems in opioid analgesia is well documented, but when and how this system is recruited to enhance pain is almost completely unknown. By elucidating mechanisms through which pro-inflammatory cytokines bring descending control systems into play, the proposed work should advance our understanding of the processes involved in pain modulation. In providing additional tools to manipulate these systems, this work may ultimately lead to improved clinical treatment of pain.
