The 5-HT6 Receptors in the Ventrolateral Orbital Cortex Attenuate Allodynia in a Rodent Model of Neuropathic Pain

Abstract

Mechanical allodynia, characterized by a painful sensation induced by innocuous stimuli, is thought to be caused by disruption in pain-related regions. Identification and reversal of this pathologic neuroadaptation are therefore beneficial for clinical treatment. Previous evidence suggests that 5-HT 6 receptors in the ventrolateral orbital cortex (VLO) are involved in neuropathic pain, but their function is poorly understood. The aim of the present study is to unveil the role of 5-HT 6 receptors in the VLO and the underlying mechanisms in pain modulation. Here, by using the spared nerve injury (SNI) pain model, first, we report that 5-HT 6 receptor protein decreased in the contralateral VLO compared with the ipsilateral VLO in rats with allodynia. Second, microinjection of the selective 5-HT 6 receptor agonists EMD-386088 and WAY-208466 into the contralateral VLO consistently and significantly depressed allodynia. Third, microinjection of the selective antagonist SB-258585 blocked the agonist-induced anti-allodynic effect, while the antagonist applied alone to the VLO had no effect. Furthermore, the anti-nociceptive effect of EMD-386088 on neuropathic pain was prevented by the adenylate cyclase (AC) inhibitor SQ-22536, and protein kinase A (PKA) inhibitor H89, suggesting that AC/PKA signaling might underlie the antinociception of agonists. Finally, the 5-HT 6 receptors were found to be colocalized with a glutamate transporter (EAAC1) by immunofluorescent staining, and the glutamate receptor antagonist kynurenic acid was found to completely block antinociception. These findings indicated that the antinociceptive effect of 5-HT 6 receptor agonists might occur via interaction with the glutamatergic system. Altogether, the agonists activated 5-HT 6 receptors present in the glutamatergic neurons in the VLO to facilitate the AC/PKA cascade, which subsequently might evoke glutamate release, thus depressing allodynia. These findings suggest a potential therapeutic role of 5-HT 6 receptor agonists in treating neuropathic pain.

Phosphorylation of Neurofilament Light Chain in the VLO Is Correlated with Morphine-Induced Behavioral Sensitization in Rats

“…The injection times, i.e., single injection of TSA versus repeated TSA injection throughout the development phase, might partially explain the discrepancy. Moreover, this result is reminiscent of other VLO studies, in which the microinjection of the 5-HT6 receptor agonist into the VLO aggregated acute inflammatory pain and attenuated chronic neuropathic pain [33,34]. Different cell types, such as glutamatergic versus GABAergic neurons, and dopamine D1 receptor-expressing (D1R) neurons versus D2R neurons, exhibited different, and even opposing effects on drug-related behaviors.…”

5-HT7 Receptor Is Involved in Electroacupuncture Inhibition of Chronic Pain in the Spinal Cord

“…Moreover, intrathecal injection of PKA inhibitor H89 30 min before EA reversed the EA effect on the tactile withdrawal thresholds. Our previous and preliminary studies found that AC inhibitor SQ22536 or PKA inhibitor H89 alone has any effect on the pain threshold in the central (Zhang et al, 2020) and spinal cord, which suggested that the AC-cAMP-PKA pathway may lack tonic activity, and the blocking effects of AC and PKA inhibitor on the EA-evoked inhibition were not a result of either compound facilitating nociceptive responses. These data further support that EA activates the spinal 5-HT 7 receptor through the Gs-AC-cAMP-PKA pathway to inhibit chronic pain in a mouse model of KOA.…”