It’s encouraging for me to see that at least some
research has already been conducted into the use of low-dose (in this case ultra
-low dose) naltrexone in the management of pain syndromes. Chronic pain -- regardless of the cause -- is a growing concern in North America and no doubt other parts of the world.
Ultra-low dose naltrexone attenuates chronic morphine-induced gliosis in rats
Theresa-Alexandra M Mattioli1, Brian Milne13 and Catherine M Cahill123*
1 Department of Pharmacology & Toxicology, Queen's University, Kingston, Ontario, K7L 3N6, Canada
2 Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, K7L 3N6, Canada
3 Department of Anaesthesiology, Kingston General Hospital, Queen's University, Kingston, Ontario, K7L 2V7, Canada
Molecular Pain 2010, 6:22 doi:10.1186/1744-8069-6-22
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance.
Spinal cord sections from rats administered chronic morphine showed significantly increased immuno-labelling of astrocytes and microglia compared to saline controls, consistent with activation. 3-D images of astrocytes from animals administered chronic morphine had significantly larger volumes compared to saline controls. Co-injection of ultra-low dose naltrexone attenuated this increase in volume, but the mean volume differed from saline-treated and naltrexone-treated controls. Astrocyte and microglial immuno-labelling was attenuated in rats co-administered ultra-low dose naltrexone compared to morphine-treated rats and did not differ from controls. Glial activation, as characterized by immunohistochemical labelling and cell size, was positively correlated with the extent of tolerance developed. Morphine-induced glial activation was not due to cell proliferation as there was no difference observed in the total number of glial cells following chronic morphine treatment compared to controls. Furthermore, using 5-bromo-2-deoxyuridine, no increase in spinal cord cell proliferation was observed following chronic morphine administration.
Taken together, we demonstrate a positive correlation between the prevention of analgesic tolerance and the inhibition of spinal gliosis by treatment with ultra-low dose naltrexone. This research provides further validation for using ultra-low dose opioid receptor antagonists in the treatment of various pain syndromes.
The results of this study may have a significant impact on the clinical management of moderate to severe pain. Patients currently treated with chronic opioid therapy may benefit not only from increased efficacy of combined opioid treatment [23,39], but may also experience fewer and less severe adverse effects [24,40], as sufficient analgesia can be achieved and maintained at lower opioid doses. Additionally, an understanding of the mechanism of action of opioid drugs will provide insight toward the development of more selective and efficacious pharmacological treatments for pain management. Not the least of which could be for improving treatment of chronic pain conditions such as neuropathic pain where glial activation is also evident, with reactive gliosis being a key contributor to the painful neuropathy [41-44]. Additionally, reduced opioid analgesic efficacy has also been reported in patients with neuropathic pain [45,46], however, co-administration of ultra-low dose antagonists with opioid agonists increased analgesic efficacy in animal models of neuropathic pain  and in clinical trials [23,24]. Future research will be required to determine if ultra-low dose naltrexone is able to alleviate established chronic pain.
Here's hoping that the "future" research mentioned in the last sentence is already underway in Canada and other countries.