5-HT1F Receptor Agonist Ameliorates Mechanical Allodynia in Neuropathic Pain via Induction of Mitochondrial Biogenesis and Suppression of Neuroinflammation.

Long-Qing Zhang,Shao-Jie Gao,Wei Mei,Ya-Qun Zhou,Jia Sun,Jia-Yi Wu,Xue-Bi Tian,Shuang Zhang,Jia-Yan Li

doi:10.3389/fphar.2022.834570

Abstract

Neuropathic pain is a devastating disease that affects millions of people worldwide. Serotonin (5-hydroxytryptamine, 5-HT) is involved in pain modulation. Several lines of evidence have indicated that 5-HT1F receptor agonists are potent inducers of mitochondrial biogenesis. In this study, we tested the hypothesis that 5-HT1F receptor agonists ameliorate mechanical allodynia in neuropathic pain via the induction of mitochondrial biogenesis and suppression of neuroinflammation. Male Sprague–Dawley rats were used to establish a neuropathic pain model via spared nerve injury (SNI). The paw withdrawal threshold (PWT) was used to evaluate mechanical allodynia. Real-time polymerase chain reaction was used to examine the mitochondrial DNA (mtDNA) copy number. Western blotting and immunofluorescence were used to examine the expression of target proteins. Our results showed that mitochondrial biogenesis was impaired in the spinal cord of rats with SNI. Moreover, activation of PGC-1α, the master regulator of mitochondrial biogenesis, attenuates established mechanical allodynia in rats with neuropathic pain. In addition, the neuronal 5-HT1F receptor is significantly downregulated in the spinal cord of rats with neuropathic pain. Furthermore, the selective 5-HT1F receptor agonist lasmiditan attenuated established mechanical allodynia in rats with neuropathic pain. Finally, lasmiditan (Las) treatment restored mitochondrial biogenesis and suppressed neuroinflammation in the spinal cord of rats with SNI. These results provide the first evidence that lasmiditan ameliorates mechanical allodynia in neuropathic pain by inducing mitochondrial biogenesis and suppressing neuroinflammation in the spinal cord. Inducers of mitochondrial biogenesis may be an encouraging therapeutic option for the management of neuropathic pain.

Highlights

Chronic neuropathic pain is a devastating disease that results from damage to or dysfunction of the nervous system (Scholz et al, 2019)
Impaired mitochondrial biogenesis has been reported to contribute to mitochondrial dysfunction in neurological diseases such as Alzheimer’s disease and spinal cord injury (Sheng et al, 2012; Scholpa et al, 2019)
We showed that 1) mitochondrial biogenesis was impaired in the spinal cord of spared nerve injury (SNI) rats; 2) activation of PGC-1α, the master regulator of mitochondrial biogenesis, attenuated established mechanical allodynia, and delayed the onset of mechanical allodynia in SNI rats; 3) neuronal 5-HT1F receptor was significantly downregulated in the spinal cord of rats with neuropathic pain; 4) lasmiditan attenuated established mechanical allodynia and delayed the onset of mechanical allodynia in SNI rats; 5) lasmiditan treatment restored mitochondrial biogenesis in the spinal cord of SNI rats; and 6) lasmiditan treatment attenuated neuroinflammation in the spinal cord of SNI rats

Summary

Introduction

Chronic neuropathic pain is a devastating disease that results from damage to or dysfunction of the nervous system (Scholz et al, 2019). It affects millions of people worldwide and severely disrupts their quality of life. It is refractory to commonly used analgesics such as nonsteroidal antiinflammatory drugs and opioids (Stacey et al, 2008). Tricyclic antidepressants and antiepileptics fail to provide sufficient pain relief. Despite rapid advances over the past few decades, the specific cellular and molecular mechanisms underlying the development of neuropathic pain remain largely unknown (Ge et al, 2020; Ruiz-Cantero et al, 2020). There is an urgent need to elucidate the pathogenesis of neuropathic pain and identify novel therapeutic targets

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