Determining 5HT7R’s Involvement in Modifying the Antihyperalgesic Effects of Electroacupuncture on Rats With Recurrent Migraine

Abstract

Electroacupuncture (EA) is widely used in clinical practice to relieve migraine pain. 5-HT7 receptor (5-HT7R) has been reported to play an excitatory role in neuronal systems and regulate hyperalgesic pain and neurogenic inflammation. 5-HT7R could influence phosphorylation of protein kinase A (PKA)- or extracellular signal-regulated kinase1/2 (ERK1/2)-mediated signaling pathways, which mediate sensitization of nociceptive neurons via interacting with cyclic adenosine monophosphate (cAMP). In this study, we evaluated the role of 5-HT7R in the antihyperalgesic effects of EA and the underlying mechanism through regulation of PKA and ERK1/2 in trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Hyperalgesia was induced in rats with dural injection of inflammatory soup (IS) to cause meningeal neurogenic inflammatory pain. Electroacupuncture was applied for 15 min every other day before IS injection. Von Frey filaments, tail-flick, hot-plate, and cold-plated tests were used to evaluate the mechanical and thermal hyperalgesia. Neuronal hyperexcitability in TNC was studied by an electrophysiological technique. The 5-HT7R antagonist (SB269970) or 5-HT7R agonist (AS19) was administered intrathecally before each IS application at 2-day intervals during the 7-day injection protocol. The changes in 5-HT7R and 5-HT7R-associated signaling pathway were examined by real-time polymerase chain reaction (RT-PCR), Western blot, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) analyses. When compared with IS group, mechanical and thermal pain thresholds of the IS + EA group were significantly increased. Furthermore, EA prevented the enhancement of both spontaneous activity and evoked responses of second-order trigeminovascular neurons in TNC. Remarkable decreases in 5-HT7R mRNA expression and protein levels were detected in the IS + EA group. More importantly, 5-HT7R agonist AS19 impaired the antihyperalgesic effects of EA on p-PKA and p-ERK1/2. Injecting 5-HT7R antagonist SB-269970 into the intrathecal space of IS rats mimicked the effects of EA antihyperalgesia and inhibited p-PKA and p-ERK1/2. Our findings indicate that 5-HT7R mediates the antihyperalgesic effects of EA on IS-induced migraine pain by regulating PKA and ERK1/2 in TG and TNC.

Effect of Xiongmatang Extract on Behavioral and TRPV1-CGRP/CGRP-R Pathway in Rats With Migraine

“…Moreover, dural inflammation is considered to be the cause of activation of trigeminal neurovascular system ( Débora et al, 2016 ). Studies have shown that the injection of inflammation soup through the dura mater could induce hyperalgesia in rats, causing meningeal neurogenic inflammatory pain sensitivity migraine and significantly reducing the mechanical pain threshold in rats ( Liu et al, 2021 ; Olivia et al, 2021 ). According to the results obtained in this study, the pain threshold of rats was significantly reduced after 2 weeks of modeling with inflammation soup.…”

“…The pain thresholdTRPV1 of frontal muscle and bilateral posterior temporal muscle was significantly reduced in migraine patients ( Rogers et al, 2020 ). Pharmacological experiments showed that the mechanical pain threshold of rats with migraine was significantly reduced ( Liu et al, 2021 ). The results of this study are consistent with these results reported in the literature.…”

“…First day, in SD rats, dura catheterization surgery was performed ( Michael and Sumittra, 2007 ; Liu et al, 2021 ). Rats were anesthetized by inhalation of isoflurane.…”

Could Experimental Inflammation Provide Better Understanding of Migraines?

“…Some other notable findings are the changes at the cellular level, and we have summarized all the below findings in supplementary tables , notably the effects in TG ( supplementary Table S1 ), brain/spinal cord ( supplementary Table S2 ) and TNC ( supplementary Table S3 ). The levels of c-Fos, a marker of neuronal activation and nociception, have been observed at higher expression levels in the TG and TNC [ 63 , 64 , 65 ]. Increases of other nociceptive and neuronal activation markers in the TGVS have been observed, such as increases in cAMP [ 64 ], PKA [ 64 ], ERK 1/2 [ 64 ], CREB [ 64 ], NGF [ 66 ], PKC [ 66 ], tyrosine receptor kinase B (TrkB) [ 67 ] and EAAT3 [ 67 ].…”

“…The levels of c-Fos, a marker of neuronal activation and nociception, have been observed at higher expression levels in the TG and TNC [ 63 , 64 , 65 ]. Increases of other nociceptive and neuronal activation markers in the TGVS have been observed, such as increases in cAMP [ 64 ], PKA [ 64 ], ERK 1/2 [ 64 ], CREB [ 64 ], NGF [ 66 ], PKC [ 66 ], tyrosine receptor kinase B (TrkB) [ 67 ] and EAAT3 [ 67 ]. Increases of inflammatory markers have also been observed in the TGVS, notably an increase in IL-1β [ 65 , 68 ], IL-18 [ 69 ], TNF-α [ 65 , 70 ], p38 [ 67 ], BDNF [ 67 ], Iκβ [ 71 ], TRIF [ 71 ], TLR4 [ 71 ], Myd88 [ 71 ] and NF-κβ [ 71 ], FKN [ 72 ], CX3CR1 [ 72 ] and PGE 2 [ 73 ].…”