Background: The development of analgesic tolerance following chronic morphine administration can be a significant\r\nclinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that\r\ninhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated\r\nthat ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical\r\nstudies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone\r\nattenuates glial activation, which may contribute to its effects on attenuating tolerance.\r\nResults: Spinal cord sections from rats administered chronic morphine showed significantly increased immunolabelling\r\nof astrocytes and microglia compared to saline controls, consistent with activation. 3-D images of astrocytes\r\nfrom animals administered chronic morphine had significantly larger volumes compared to saline controls. Coinjection\r\nof ultra-low dose naltrexone attenuated this increase in volume, but the mean volume differed from salinetreated\r\nand naltrexone-treated controls. Astrocyte and microglial immuno-labelling was attenuated in rats coadministered\r\nultra-low dose naltrexone compared to morphine-treated rats and did not differ from controls. Glial\r\nactivation, as characterized by immunohistochemical labelling and cell size, was positively correlated with the extent of\r\ntolerance developed. Morphine-induced glial activation was not due to cell proliferation as there was no difference\r\nobserved in the total number of glial cells following chronic morphine treatment compared to controls. Furthermore,\r\nusing 5-bromo-2-deoxyuridine, no increase in spinal cord cell proliferation was observed following chronic morphine\r\nadministration.\r\nConclusion: Taken together, we demonstrate a positive correlation between the prevention of analgesic tolerance and\r\nthe inhibition of spinal gliosis by treatment with ultra-low dose naltrexone. This research provides further validation for\r\nusing ultra-low dose opioid receptor antagonists in the treatment of various pain syndromes
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