In vivophotopharmacology with light-activated opioid drugs

Abstract

Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using caged opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed PhOX and PhNX, photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry during chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action.

Nucleus accumbens sub-regions experience distinct dopamine release responses following acute and chronic morphine exposure

“…The existing literature on dopamine release in chronic opioid models is rife with contradictions and methodological caveats. Some work has found diminished responses that align with the traditional views of opioid tolerance (Mazei-Robison et al, 2011;McClain et al, 2023) while others have observed unchanged dopamine tone (Pothos et al, 1991) or even sensitization when responses in the NAc core are measured (Lefevre et al, 2020). The contrast of all these data highlights the ever-present trade-offs between mechanistic specificity and human relevance in our models and emphasizes the need to approach these questions with multiple experimental strategies.…”