Details

Autor(en) / Beteiligte

• Smith, Alexander C. W.
• Ghoshal, Soham
• Centanni, Samuel W.
• Heyer, Mary P.
• Corona, Alberto
• Wills, Lauren
• Andraka, Emma
• Lei, Ye
• O’Connor, Richard M.
• Caligiuri, Stephanie P. B.
• Khan, Sohail
• Beaumont, Kristin
• Sebra, Robert P.
• Kieffer, Brigitte L.
• Winder, Danny G.
• Ishikawa, Masago
• Kenny, Paul J.

Titel

A master regulator of opioid reward in the ventral prefrontal cortex

Ist Teil von

• Science (American Association for the Advancement of Science), 2024-06, Vol.384 (6700), p.eadn0886

Ort / Verlag

Washington: The American Association for the Advancement of Science

Erscheinungsjahr

2024

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping in mice to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone. Connectomic profiling revealed that DPn neurons innervate the parabrachial nucleus (PBn). Spatial and single-nuclei transcriptomics resolved a population of PBn-projecting pyramidal neurons in the DPn that express μ-opioid receptors (μORs). Disrupting μOR signaling in the DPn switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings identify the DPn as a key substrate for the abuse liability of opioids. Editor’s summary Opioids that engage μ-opioid receptor signaling in the brain are highly addictive, but in addition to their rewarding effects, opioids can also be highly aversive. How the rewarding and aversive effects of opioids interact in the brain to control addiction-related behaviors is poorly understood. Smith et al . identified regions exhibiting modified neural activity in response to a rewarding dose of oxycodone. In addition to well-established regulators of physiological and behavioral responses to opioids, neural activity in the dorsal peduncular nucleus, a relatively unexplored area in the ventral prefrontal cortex, was also highly opioid responsive. A population of unusual glutamatergic neurons that were spatially restricted to the dorsal peduncular nucleus encoded states of aversion and were directly inhibited by opioids. —Peter Stern INTRODUCTION Misuse of opioids for their rewarding effects has contributed to an unprecedented surge in drug overdose–related deaths in the United States. Opioids stimulate μ-opioid receptors (μORs) in the ventral tegmental area (VTA) to enhance mesolimbic dopamine transmission. This action is thought to play a crucial role in opioid reward. μORs located outside the mesolimbic system also contribute to the addiction-related actions of opioids, but relatively little is known about these dopamine-independent mechanisms. Paradoxically, opioids can be highly aversive, even at the same doses that elicit rewarding effects. Aversion to opioids protects against their misuse and reduces the risk of developing opioid use disorder (OUD). How the rewarding and aversive effects of opioids interact in the brain to influence vulnerability to OUD is poorly understood. RATIONALE We hypothesized that neurons involved in opioid reward and aversion would show altered activity in mice after injection with the prescription opioid oxycodone (OxyContin). Using whole-brain mapping of the immediate early gene product c-Fos, we found that oxycodone increased neural activity in the dorsal peduncular nucleus (DPn), a relatively unexplored region of the ventral prefrontal cortex. Optically simulating neuronal activity in the DPn elicited an aversive behavioral state that was blocked by oxycodone injection. These findings prompted us to investigate the role of DPn neurons in regulating positive and negative hedonic reactions to opioids. RESULTS Using FosTRAP2 mice, channelrhodopsin was expressed only in DPn neurons whose activity was increased by injection of a rewarding dose of oxycodone. Optically stimulating these neurons induced an aversive behavioral state, suggesting that the DPn regulates negative reactions to opioids. FosTRAP2 mice were used to fluorescently label oxycodone-activated DPn neurons. Whole-brain mapping of labeled axons showed that these neurons innervate the parabrachial nucleus (DPn→PBn neurons). Single-cell connectomic mapping confirmed that opioid-regulated DPn neurons innervate the PBn and showed that a large proportion of these same neurons also project to the VTA. Optically stimulating the terminals of opioid-activated DPn neurons in the PBn evoked an aversive behavioral state. High-resolution spatial transcriptomics was used to profile neurons in the DPn and surrounding cortical regions. This resolved a rare population of cortical pyramidal neurons largely restricted to the DPn that express vesicular glutamate transport 2 (DPn vGlut2 neurons), which is usually expressed only by subcortical glutamatergic neurons. Circuit tracing showed that DPn vGlut2 neurons project the PBn. Optically stimulating DPn vGlut2 neurons precipitated an aversive state reversible by oxycodone injection. Single-nuclei RNA sequencing and in situ hybridization revealed that DPn vGlut2 neurons express μORs, which in the cortex are typically expressed by inhibitory γ-aminobutyric acid–mediated interneurons. Using whole-cell electrophysiological recordings, we found that opioids act on DPn vGlut2 neurons to decrease their excitability. Furthermore, optically stimulating the terminals of DPn vGlut2 neurons increased excitatory glutamatergic signaling in the PBn, which was inhibited by opioids. When μORs were genetically ablated from DPn neurons, the locomotor stimulant effect of oxycodone, which is known to be mediated by mesolimbic dopamine transmission, was unaltered. However, ablation of μORs from DPn neurons rendered an otherwise rewarding dose of oxycodone aversive. Finally, optically stimulating DPn neurons or genetically ablating μORs from these cells increased the intensity of opioid withdrawal in oxycodone-dependent mice, whereas chemogenetically silencing DPn neurons attenuated opioid withdrawal. CONCLUSION Our study identifies a population of excitatory neurons in the DPn that project to the PBn. These DPn→PBn neurons are distinguishable from other cortical glutamatergic neurons by their atypical expression of vGlut2 and μORs. Activation of DPn→PBn neurons contributes to aversive reactions to opioids. The activity of DPn→PBn aversion neurons is constrained by a direct inhibitory effect of opioids on these cells. Eliminating the direct inhibitory influence of opioids on DPn→PBn neurons renders opioids highly aversive. In opioid-dependent animals, the activity of DPn neurons also contributes to aversive symptoms of opioid withdrawal. Together, these findings suggest that DPn neurons are critically involved in key actions of opioids that contribute to the development and maintenance of OUD. DPn neurons that express vGlut2 and μORs project to the PBn and encode states of aversion. Opioids exert a direct inhibitory effect on these DPn→PBn neurons. Disrupting μOR signaling in the DPn disinhibits aversive reactions to opioids and exacerbates the severity of withdrawal in opioid-dependent animals. [Created with Biorender.com]