UC San Diego

Understanding the neural circuitry of the opioid system in the brain is a pressing clinical and scientific problem. Endogenous opioids are implicated in myriad behavioral functions including reward and analgesia. In a clinical setting, widely used opioid drugs can produce dangerous off-target effects including addiction and death. Pharmacology has long been used as a blunt tool of neuroscientists and clinicians for manipulating the central nervous system. The diverse effects of systemic opioids on the central nervous system (CNS) and the pitfalls of their clinical use highlight the need for advances in pharmacological tools. Photopharmacology, or the activation of drugs using light, is a potential innovation that will allow for new avenues of inquiry in the study of neural circuits. However, applying photopharmacology to study neural circuits in vivo has not been previously demonstrated as feasible. I show that we have developed a photoactivable opioid agonist, PhOX and antagonist, PhNX as a tool-kit for bidirectional manipulation of opioid receptors in vivo. First, I demonstrate that photoactivation of these compounds produces spatial and temporally specific effects on opioid receptor binding, behavior, and neural activity in vivo. Next, I apply photopharmacology to answer questions about opioid-dopamine interactions. Using same-site photoactivation and calcium monitoring in the Ventral Tegmental Area, I demonstrate, for the first time in vivo, suppression of inhibitory terminals by opioids. Finally, I use photopharmacology to study changes in mesolimbic circuitry under chronic morphine conditions.