(+)-Naloxone

Relation with opioids

Both active and inactive enantiomers of various opioid analgesic drugs including morphine, meperidine, fentanyl, methadone and buprenorphine, as well as some otherwise inactive metabolites like morphine-3-glucuronide, have been found to act as agonists of TLR4, and chronic use of these drugs consequently causes constant low-level release of TNF-α and IL-1β as well as other downstream effects. This is thought to be involved in various adverse properties of opioid analgesic drugs, such as loss of efficacy with extended use and the associated development of tolerance and dependence, as well as the development of side effects such as hyperalgesia and allodynia, which can cause long-term use of opioid analgesics to not only fail to treat neuropathic pain, but ultimately exacerbate it.

Applications of (+)-naloxone and related drugs

Several opioid antagonist drugs were found to act as antagonists for TLR4, including naloxone and naltrexone. However it was found that not only the (−) enantiomers, but also the (+) enantiomers of these drugs acted as TLR4 antagonists (though (+)-nalmefene was inactive). Since (+)-naloxone and (+)-naltrexone lack affinity for opioid receptors, they do not block the effects of opioid analgesic drugs, and so can be used to counteract the TLR4-mediated side effects of opioid agonists without affecting analgesia, though (+)-naloxone does reduce the reinforcing effects of opioid drugs. (+)-Naloxone was also found to be neuroprotective, and both (+)-naloxone and (+)-naltrexone are effective in their own right at treating symptoms of neuropathic pain in animal models. However (+)-naloxone was also found to reduce the effects of stimulant drugs, suggesting additional actions beyond TLR4 antagonism (possibly as a sigma receptor antagonist), that might potentially result in unwanted side effects or drug interactions.

References

References

1. (April 1978). "Studies in the (+)-morphinan series. 5. Synthesis and biological properties of (+)-naloxone". Journal of Medicinal Chemistry.
2. (September 2005). "Antianalgesia: stereoselective action of dextro-morphine over levo-morphine on glia in the mouse spinal cord". The Journal of Pharmacology and Experimental Therapeutics.
3. (November 2009). "The "toll" of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia". Trends in Pharmacological Sciences.
4. (January 2010). "Evidence that opioids may have toll-like receptor 4 and MD-2 effects". Brain, Behavior, and Immunity.
5. (May 2010). "Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences". Neuroscience.
6. (November 2006). "dextro-Naloxone or levo-naloxone reverses the attenuation of morphine antinociception induced by lipopolysaccharide in the mouse spinal cord via a non-opioid mechanism". The European Journal of Neuroscience.
7. (August 2012). "Opioid activation of toll-like receptor 4 contributes to drug reinforcement". The Journal of Neuroscience.
8. (May 2000). "Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation". The Journal of Pharmacology and Experimental Therapeutics.
9. (September 2002). "Inhibition by naloxone stereoisomers of beta-amyloid peptide (1-42)-induced superoxide production in microglia and degeneration of cortical and mesencephalic neurons". The Journal of Pharmacology and Experimental Therapeutics.
10. (July 2008). "Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4)". The European Journal of Neuroscience.
11. (May 2012). "(+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats". The Journal of Pain.
12. (June 1996). "Prevention of cocaine-induced hyperactivity by a naloxone isomer with no opiate antagonist activity". Neurochemical Research.
13. (February 1998). "Dextro-naloxone counteracts amphetamine-induced hyperactivity". Pharmacology, Biochemistry, and Behavior.
14. (October 2007). "Stereoselective action of (+)-morphine over (−)-morphine in attenuating the (−)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse". European Journal of Pharmacology.