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Low‐Dose 6β‐Naltrexol Prevents Opioid Dependence Without Affecting Antinociception

We asked whether opioid dependence can be prevented during opioid pain therapy or maintenance therapy of opioid use disorder. We hypothesize that 6β‐naltrexol (6BN) binds to the basally activated μ opioid receptor (MOR) prevalent in dependence and gradually reverts it to its resting state, proposing a novel MOR model (1). Clinical utility of opioid analgesics is compromised by adverse effects and addiction liability, largely mediated by MOR, which displays spontaneous basal activity. It’s upregulation by opioid agonists can contribute to opioid dependence. Acting as inverse MOR antagonists in the dependent state, naltrexone and naloxone cause withdrawal at exceedingly low doses. We had identified 6β‐naltrexol (6BN) as a neutral MOR antagonist, which blocks antinociception and causes withdrawal only at much higher doses, even though its MOR affinity equals that of naltrexone. Weak antagonist potency of 6BN is due to both its neutral antagonism and peripheral selectivity because of slow entry into the brain. Nevertheless, low‐dose 6BN (LD‐6BN; <0.1 mg/kg) potently prevents the development of dependence in adult guinea pigs treated with methadone (6BN IC50=~0.01 mg/kg), presumably a central effect (2). To test whether LD‐6BN establishes meaningful 6BN levels in the brain, we measure blood and brain levels with a highly sensitive mass spectrometry assay. Following an s.c. 6BN dose of 0.02 mg/kg in guinea pigs, blood levels initially exceed brain levels tenfold, consistent with its peripheral selectivity, followed by rapid elimination from blood (t1/2 ~1h). In contrast, 6BN levels increased over 2h and persisted in brain for 8h at 1‐2 nM levels (t1/2 ~5h). Co‐administration of a saturating naloxone dose reduced 6BN brain levels by ~70% at 1‐3h, indicating saturable high affinity binding. The results show that LD‐6BN reaches central opioid receptor sites by slow penetration and long retention in the brain, enabling a possible gradually reversal of upregulated basal MOR activity. LD‐6BN appears to act as a dependence modulator rather than a typical opioid antagonist, accounting for its prevention of opioid dependence during agonist treatment, and possibly other aspects of opioid addiction.