Reported Benefits of Low-Dose Naltrexone Appear to Be Independent of the Endogenous Opioid System Involving Proopiomelanocortin Neurons and Beta-Endorphin

Naltrexone is an opioid receptor antagonist approved for the treatment of alcohol and opioid use disorders at doses of 50-150 mg per day. Naltrexone has also been prescribed at much lower doses (3-6 mg per day) for the off-label treatment of inflammation and pain. Currently, a compelling mechanistic explanation for the reported efficacy of low dose naltrexone (LDN) is lacking and none of the proposed mechanisms can explain patient reports of improved mood and sense of well-being. Here, we examined the possibility that LDN might alter the activity of the endogenous opioid system involving proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus in male and female mice. Known actions of POMC neurons could account for changes in pain perception and mood. However, using electrophysiologic, imaging and peptide measurement approaches, we found no evidence for such a mechanism. LDN did not change the sensitivity of opioid receptors regulating POMC neurons, the production of the beta-endorphin precursor Pomc mRNA, nor the release of beta-endorphin into plasma. Spontaneous post-synaptic currents onto POMC neurons were slightly decreased after LDN treatment and GCaMP fluorescent signal, a proxy for intracellular calcium levels, was slightly increased. However, LDN treatment did not appear to change POMC neuron firing rate, resting membrane potential, nor action potential threshold. Therefore, LDN appears to have only slight effects on POMC neurons that do not translate to changes in intrinsic excitability or baseline electrical activity and mechanisms beyond POMC neurons and altered opioid receptor sensitivity should continue to be explored. Significance Statement Naltrexone blocks opioid receptor activity and is used for the treatment of alcohol and opioid use disorders but is also prescribed at lower doses to treat inflammation and pain. A compelling mechanistic explanation for the reported efficacy of low dose naltrexone (LDN) is lacking, and understanding the central effects of LDN is important, both for basic science and to inform future applications of LDN for central disorders. We hypothesized that LDN might alter the activity of endogenous opioid systems in proopiomelanocortin (POMC) neurons of the hypothalamus. However, we found no evidence for such a mechanism and LDN appears to only slightly affect POMC neurons. We conclude that future studies should shift focus to other opioid systems outside of POMC neurons.