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The present studies used the classical method of serial transections of the neuraxis to examine the neural mechanisms of injury-produced pain and morphine analgesia in the formalin test. The results showed that the behavioral response that follows formalin injection is complete within the brainstem, whereas telencephalic structures are critical for morphine to produce analgesia. In contrast, when the tail flick test, a model of noninjurious pain was used, both the behavioral response, and analgesia, were intact in the brainstem transected rat, in keeping with the current model of analgesia for this test. Brain areas classically associated with pain processing were not sufficient for morphine to produce analgesia in the formalin test. Instead, the amygdala, part of the emotion-mediating limbic system, was critical. It is argued that the formalin test may be a model of "dissociative" analgesia, in which reduction of the negative affective consequences of the pain plays a major role.

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published_or_final_version / Physiology / Master / Master of Philosophy

Previous studies in our laboratory have indicated that anesthetic block of neural activity at discrete sites within the limbic system, including the lateral hypothalamus and anterior cingulum bundle, causes a significant long-lasting analgesia during the formalin test. In this experiment, the local anesthetic lidocaine was microinjected into the dentate region of the hippocampus, an important limbic structure presumed to subserve the affective-motivational aspects of pain. The dentate gyrus is strategically situated at a point of convergence of widespread polysensory cortical input to the hippocampus, to allow modulation of cortical signals before they diverge into numerous limbic circuits. The results indicate that anesthetic block of the anterior region of the dentate gyrus produces analgesia in the rat during the formalin test. The analgesia produced by this procedure became apparent 30 minutes after regional block contralateral to the site of injury and persisted for the duration of the test period. These data provide further evidence that limbic forebrain structures are involved in pain and analgesia.

The hypothalamic-pituitary-adrenal (HPA) axis, a system activated by stress, is traditionally considered to affect the susceptibility to chronic pain via effects on peripheral processes. This study investigates whether the HPA axis contributes to the development of chronic pain in an animal model via direct effects on central pain mechanisms. / First, correlations between pain processes and the susceptibility to chronic pain in an animal model that is correlated with HPA-axis function were examined. The results show that, in the Fischer rat, the amount of pain suppression observed during the formalin interphase depression is negatively correlated with susceptibility to polyarthritis. Since the formalin interphase depression mechanisms are within the central nervous system, the results suggest a role for central pain mechanisms in the development of polyarthritis. / Hypophysectomy inhibits the development of adjuvant-induced arthritis. To test whether hypophysectomy inhibits adjuvant-induced polyarthritis via central pain mechanisms, the analgesic effect of hypophysectomy was examined in the formalin test. The results show that hypophysectomy specifically prolongs the formalin interphase depression, further supporting that the underlying central pain suppression mechanisms are associated with resistance to adjuvant-induced polyarthritis. / Corticotropin-releasing factor (CRF) was then investigated as a possible underlying mechanism of the effects of hypophysectomy. Peripheral injection of CRF into inflamed tissue affects pain mechanisms unrelated to the susceptibility to adjuvant-induced polyarthritis. However, central and intravenous administration of CRF preferentially affect the formalin interphase depression mechanisms. The observed dose-response relationships indicate that these effects are due to direct actions of CRF within the central nervous system. / In conclusion, the results strongly suggest that the HPA axis modulates the susceptibility to adjuvant-induced polyarthritis via direct effects on supraspinal pain suppression mechanisms. Thus, the HPA axis may contribute to the development of chronic pain syndromes associated with HPA-axis abnormalities, such as rheumatoid arthritis and fibromyalgia, via effects on pain mechanisms within the central nervous system.

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This thesis investigated the contribution of descending fibers from the rostral ventromedial medulla (RVM) to nociception, and to opioid and non-opioid analgesia in rats. Inactivation of descending fibers was induced by microinjection of the GAGA-A agonist muscimol in the RVM, and nociception was evaluated using the tail immersion, hot plate and formalin tests. In all three tests, microinjection of muscimol (6.25--400 ng) in the RVM increased nociceptive responses of animals, suggesting that descending fibers tonically inhibit dorsal horn neurons of the spinal cord. In the formalin test, microinjection of muscimol (50 ng) in the RVM reduced the slope of the formalin concentration-response relation, so that responses were increased at low, but not at high concentrations of formalin. Conversely, microinjection of the GABA-A antagonist bicuculline in the RVM decreased the slope of the formalin concentration-response relation, so that responses were decreased at high but not at low concentrations of formalin. Microinjection of muscimol in the RVM abolished analgesia induced by systemic morphine in the tail immersion and hot plate tests, but only decreased analgesia by 60% in the formalin test. Microinjection of muscimol (50 ng) in the RVM abolished morphine analgesia elicited intracerebroventricularly, suggesting that the supraspinal effects of morphine are mediated via descending fibers from the RVM. Peripheral effects may account for the residual analgesic effect of systemic morphine after inactivation of descending fibers in the formalin test. Microinjection of muscimol (50 ng) in the RVM abolished buprenorphine analgesia in all tests. The dopamine uptake inhibitor nomifensine was devoid of analgesic activity in the tail immersion and hot plate tests. In the formalin test, nomifensine produced a dose-dependent analgesia, which was not affected by the microinjection of muscimol (50 ng) in the RVM. It is concluded that, descending fibers from the RVM tonically inhib

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