Abstract
The amygdala plays a key role in emotional-affective aspects of pain and in pain modulation. The central nucleus (CeA) serves major amygdala output functions related to emotional-affective behaviors and pain modulation. Our previous studies implicated the corticotropin-releasing factor (CRF) system in amygdala plasticity and pain behaviors in an arthritis model. We also showed that serotonin (5-HT) receptor subtype 5-HT2CR in the basolateral amygdala (BLA) contributes to increased CeA output and neuropathic pain-like behaviors. Here, we tested the novel hypothesis that 5-HT2CR in the BLA drives CRF1 receptor activation to increase CeA neuronal activity in neuropathic pain. Extracellular single-unit recordings of CeA neurons in anesthetized adult male rats detected increased activity in neuropathic rats (spinal nerve ligation model) compared to sham controls. Increased CeA activity was blocked by local knockdown or pharmacological blockade of 5-HT2CR in the BLA, using stereotaxic administration of 5-HT2CR short hairpin RNA (shRNA) viral vector or a 5-HT2CR antagonist (SB242084), respectively. Stereotaxic administration of a CRF1 receptor antagonist (NBI27914) into the BLA also decreased CeA activity in neuropathic rats and blocked the facilitatory effects of a 5-HT2CR agonist (WAY161503) administered stereotaxically into the BLA. Conversely, local (BLA) knockdown of 5-HT2CR eliminated the inhibitory effect of NBI27914 and the facilitatory effect of WAY161503 in neuropathic rats. The data suggest that 5-HT2CR activation in the BLA contributes to neuropathic pain-related amygdala (CeA) activity by engaging CRF1 receptor signaling.
Highlights
Serotonin (5-HT) plays an important role in pain modulation and can have facilitatory and inhibitory effects depending on the site of action in the nervous system, cell type, and receptor subtype and affinity [1,2,3,4]
The results suggest that corticotropin-releasing factor 1 (CRF1) receptor activation downstream of 5-HT2C receptor (5-HT2CR) contributes to increased activity of central nucleus (CeA) neurons in a neuropathic pain model
The experiments described here were designed to analyze the interaction between serotonin receptor 5-HT2CR in the basolateral amygdala (BLA) and corticotropin-releasing factor receptor CRF1 signaling downstream of 5-HT2CR and their contribution to the increased activity of the central amygdala (CeA) neurons in a neuropathic pain model
Summary
Serotonin (5-HT) plays an important role in pain modulation and can have facilitatory and inhibitory effects depending on the site of action in the nervous system, cell type, and receptor subtype and affinity [1,2,3,4]. The Gq-coupled 5-HT2C receptor (5-HT2CR) has been implicated in adverse (anxiogenic) effects of SSRIs [13] and their inconsistent efficacy in neuropathic pain [14]. Overexpression of 5-HT2CR is found in glutamatergic neurons in the amygdala and other brain areas in calmodulin-dependent protein kinase IIα-2C receptor (CaMKIIα–2CR) transgenic mice [24], and increased 5-HT2CR expression in the BLA using recombinant adenovirus-containing 5-HT2CR sense sequence [25] resulted in increased anxiety-like behaviors in the elevated plus maze (EPM) and open field test (OFT), which was independent of hypothalamic–pituitary–adrenal (HPA) axis activity [25]. Pharmacologic activation of 5-HT2CR in the BLA, but not CeA, had anxiogenic effects in the elevated T-maze, light-dark test and OFT [15,27], and induced ultrasonic vocalizations [27]. A 5-HT2A/2CR antagonist (ritanserin) prevented anxiogenic effects of a systemic 5-HT2CR agonist on the EPM [29]
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