Neuropathic pain after chronic nerve constriction may not correlate with chloride dysregulation in mouse trigeminal nucleus caudalis neurons.

Changes in chloride reversal potential in rat spinal cord neurons have previously been associated with persistent pain in nerve injury and inflammation models. These changes correlate with a decrease in the expression of the potassium chloride transporter, KCC2, and with increases in neuronal excitability. Here, we test the hypothesis that similar changes occur in mice with neuropathic pain induced by chronic constriction injury of the trigeminal infraorbital nerve (CCI-ION). This model allows us to distinguish an acute pain phase (3-5 days after injury) from a persistent pain phase (12-14 days after CCI-ION). Chronic constriction injury of the trigeminal infraorbital nerve induced significant decreases in mechanical pain thresholds in both the acute and persistent phases. To estimate GABAA reversal potentials in neurons from trigeminal nucleus caudalis, we obtained perforated patch recordings in vitro. GABAA reversal potential decreased by 8% during the acute phase in unidentified neurons, but not in GABAergic interneurons. However, at 12 to 14 days after CCI-ION, GABAA reversal potential recovered to normal values. Quantitative real-time polymerase chain reaction analysis revealed no significant changes, at either 3 to 5 days or 12 to 14 days after CCI-ION, in either KCC2 or NKCC1. These findings suggest that CCI-ION in mice results in transient and modest changes in chloride reversal potentials, and that these changes may not persist during the late phase. This suggests that, in the mouse model of CCI-ION, chloride dysregulation may not have a prominent role in the central mechanisms leading to the maintenance of chronic pain.

Fluoxetine exposure during adolescence alters responses to aversive stimuli in adulthood.

The mechanisms underlying the enduring neurobiological consequences of antidepressant exposure during adolescence are poorly understood. Here, we assessed the long-term effects of exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, during adolescence on behavioral reactivity to emotion-eliciting stimuli. We administered FLX (10 mg/kg, bi-daily, for 15 d) to male adolescent [postnatal day 35 (P35) to P49] C57BL/6 mice. Three weeks after treatment (P70), reactivity to aversive stimuli (i.e., social defeat stress, forced swimming, and elevated plus maze) was assessed. We also examined the effects of FLX on the expression of extracellular signal-regulated kinase (ERK) 1/2-related signaling within the ventral tegmental area (VTA) of adolescent mice and Sprague Dawley rats. Adolescent FLX exposure suppressed depression-like behavior, as measured by the social interaction and forced swim tests, while enhancing anxiety-like responses in the elevated plus maze in adulthood. This complex behavioral profile was accompanied by decreases in ERK2 mRNA and protein phosphorylation within the VTA, while stress alone resulted in opposite neurobiological effects. Pharmacological (U0126) inhibition, as well as virus-mediated downregulation of ERK within the VTA mimicked the antidepressant-like profile observed after juvenile FLX treatment. Conversely, overexpression of ERK2 induced a depressive-like response, regardless of FLX pre-exposure. These findings demonstrate that exposure to FLX during adolescence modulates responsiveness to emotion-eliciting stimuli in adulthood, at least partially, via long-lasting adaptations in ERK-related signaling within the VTA. Our results further delineate the role ERK plays in regulating mood-related behaviors across the lifespan.