Physiologically distinct neurons within the ventrolateral periaqueductal gray are not defined by mu-opioid receptor expression but are differentially activated by persistent inflammation

The ventrolateral periaqueductal gray (vlPAG) is a key structure within the descending pain modulatory pathway and an important target for opioid-induced analgesia. This area contains heterogeneous neurons with respect to neurotransmitter and receptor expression so it is difficult to define vlPAG neurons that contribute to pain and analgesia. Characterization of intrinsic membrane properties of 371 vlPAG neurons from female and male Long-Evans rats identified 4 neuron types with distinct intrinsic firing patterns: Phasic, Tonic, Onset, and Random. Phasic and Tonic neurons comprise the majority of the neurons sampled. Mu-opioid receptor (MOR) expression was determined by the ability of the 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 in naive rats and in rats pretreated with Complete Freund's adjuvant in a hindpaw to produce persistent inflammation. The presence of low threshold spikes (LTS) did not correlate with MOR-mediated GIRK currents indicating that MOR expression alone does not define a physiologically distinct neuron type in the vlPAG. MOR activation inhibited firing in nearly all spontaneously active neurons, both in naive and persistent inflammation conditions. CFA-induced inflammation increased Fos expression at both acute (2 h) and persistent inflammation (5-7 d) time points. However, persistent, but not acute, inflammation selectively enhanced spontaneous firing and lowered firing thresholds of Phasic neurons which was maintained in the absence of synaptic inputs. Taken together, persistent inflammation selectively activates Phasic neurons, of which only a subset was opioid-sensitive.