LAUSR

The ventrolateral periaqueductal gray (vlPAG) is a key brain area within the descending pain modulatory pathway and an important target for opioid-induced analgesia. The vlPAG contains heterogeneous neurons with respect to neurotransmitter content, receptor and channel expression, and in vivo response to noxious stimuli. This study characterizes intrinsic membrane properties of vlPAG neurons to identify which neuron types respond to inflammation and determine whether the pain-responsive neurons are inhibited by opioids. Surveying 382 neurons identified 4 neuron types with distinct intrinsic firing patterns: Phasic (48%), Tonic (33%), Onset (10%), and Random (9%). Mu-opioid receptor (MOR) expression was determined by the ability of a selective MOR agonist (DAMGO) to activate G protein-coupled inwardly-rectifying potassium channel (GIRK) currents. Opioid-sensitive and -insensitive neurons were observed within each neuron type, except Random neurons which were all opioid-sensitive. Opioid sensitivity did not correlate with other intrinsic firing features, including low-threshold spiking that has been previously proposed to identify opioid-sensitive GABAergic neurons in the vlPAG of mice. Complete Freunds Adjuvant (CFA)-induced acute inflammation (2 h) had no effect on vlPAG neuron firing. However, persistent inflammation (5-7 d) selectively activated Phasic neurons through a significant reduction in their firing threshold. Further evaluation uncovered that the opioid-sensitive neurons were strongly activated compared to the opioid-insensitive Phasic neurons. Overall, these findings provide a new target to investigate the time-dependent mechanisms driving selective Phasic neuron activation by inflammation. Furthermore, this study provides a framework to identify cell-type-specific pharmacological manipulations to reverse the physiological activation induced by persistent inflammatory pain states.