We were the first to prepare and characterize unnatural (+)-naloxone (1978) and (+)-naltrexone (1997) as opioid receptor inert research tools useful for detecting opioid receptor mediated effects when used in conjunction with (-)-naloxone and (-)-naltrexone, both high affinity clinical useful narcotic antagonists. We know now that (+)-naloxone and (+)-naltrexone, long thought to be inert compounds, are functional antagonists of Toll-like 4 (TLR-4) receptors and that selective acute functional antagonism of TLR-4 by (+)-naloxone and (+)-naltrexone results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Earlier we introduced the concept of toll-like receptor mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation was demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. We have now extended our studies of TLR4 antagonism to the physiological process of birth (parturition). Prior work had shown that an inflammatory response is instrumental in parturition but the upstream signals initiating inflammation have not been defined. Endogenous ligands for TLR4 receptors are released in late gestation, so we examined the possibility that on-time labor requires TLR4 signaling to trigger a cytokine and leukocyte response and accelerate the parturition cascade. We found that (+)-naltrexone-induced TLR4 antagonism increased the mean gestation period in wild type mice by 16 hours vs normal controls. These and other data including that from TLR4 deficient mice demonstrate that TLR4 is a key upstream regulator of the inflammatory response acting to drive uterine activation and control the timing of labor. Since causal pathways for term and preterm labor converge with TLR4, interventions to manipulate TLR4 signaling may have therapeutic utility for women at risk of preterm labor, or in post-term pregnancy.
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