Research Review: Ketamine Metabolite Reduces Anxiety-Like Behaviors Associated with Morphine Withdrawal

A recent study found that ketamine metabolite (2R,6R)-hydroxynorketamine effectively reduces anxiety-like behaviors associated with morphine withdrawal in mice by modulating neuronal excitability and potassium channel activity in the brain.

For individuals struggling with opioid addiction, the unpleasant anxiety and dysphoric symptoms that accompany withdrawal can be a major driver of relapse. New research has identified a novel mechanism by which a metabolite of the anesthetic drug ketamine can rapidly alleviate these withdrawal-related anxiety symptoms in male mice.

In the study, researchers explored how a metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), could alleviate anxiety-like behaviors seen in male mice after morphine withdrawal. They centered on the role of parvalbumin (PV) neurons in the nucleus accumbens shell (sNAc), a brain region crucial for emotion regulation.

PV neurons are a special class of inhibitory interneurons that regulate activity of the nucleus accumbens, a key region involved in addiction, anxiety and reward processing.

The researchers found that after chronic morphine exposure and withdrawal in male mice, the intrinsic excitability of sNAc PV neurons became abnormally increased due to changes in potassium channel function. This heightened PV neuron activity appeared to drive the expression of anxiety-like behaviors during opioid withdrawal.

Remarkably, systemic administration of (2R,6R)-hydroxynorketamine (HNK) - a metabolite of the rapid-acting antidepressant ketamine - was able to reverse the aberrant excitability of sNAc PV neurons and quickly alleviate anxiety in the morphine-withdrawn mice within about an hour.

Key Findings:

• Morphine withdrawal led to increased excitability of sNAc PV neurons, contributing to anxiety-like behaviors.

• (2R,6R)-HNK treatment significantly improved these behaviors by reducing the excitability of these neurons.

• The beneficial effects of (2R,6R)-HNK were linked to its ability to enhance potassium (K+) currents in sNAc PV neurons, pointing to a direct action on neuronal excitability.

Using chemogenetic techniques to selectively inhibit or activate the sNAc PV neurons provided further evidence that modulating their activity bidirectionally controls withdrawal-induced anxiety states. Inhibiting PV neurons reduced anxiety, while activating them promoted anxiety-like behaviors even in non-withdrawn mice.

The Implications:

This study provides insight into the neural mechanisms underlying morphine withdrawal-induced anxiety and suggests that targeting sNAc PV neurons with (2R,6R)-HNK could offer a rapid and effective treatment strategy for anxiety disorders and opioid addiction. This newly identified mechanism could potentially be leveraged for developing improved therapies to manage opioid withdrawal and prevent relapse driven by negative affective states.

Further Notes:

Ketamine itself has been shown to have rapid antidepressant effects in various studies, and its metabolite (2R,6R)-HNK is believed to contribute to these effects without some of ketamine's undesirable side effects, such as dissociation and potential for abuse. The findings from this study suggest that while (2R,6R)-HNK, a metabolite of ketamine, has a beneficial effect on morphine withdrawal-induced anxiety, it might indicate a broader potential for ketamine and its metabolites in treating withdrawal symptoms and perhaps even in addiction therapy.

However, it's important to note that the direct effects of ketamine on opioid withdrawal symptoms would need to be studied separately, as this study specifically focused on (2R,6R)-HNK. The mechanisms of action between ketamine and its metabolite can differ, so while the findings are promising for (2R,6R)-HNK, one cannot automatically conclude that ketamine itself would have the same effects without direct evidence.

Read the full study here.