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Gene & Protein in Disease GPER1 in brain and heart diseases

and neuroinflammation responses in neuropathic Activation of GPER1 through G-1 significantly reduced
pain. In a previous study, GPER1 was expressed in the the anxiety-like behavior but did not alter thermal
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anterior cingulate cortex where it mediated exacerbated hyperalgesia or mechanical allodynia. Mechanistically,
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neuropathic pain in an OVX female mouse model and this study revealed a role of GPER1 in maintaining the
induced estrogen-mediated visceral hypersensitivity in a balance between excitatory and inhibitory transmissions
stressed rat model. In another study, although estrogen in the basolateral amygdala synapses of OVX female
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levels were higher in females, GPER1 was expressed mice suffering from chronic pain. Liverman et al.
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in the dorsal root ganglia and afferent terminals in showed that GPER1 expression is upregulated through
the dorsal horn of male and female rats. Araldi et al. inflammatory processes, suggesting that GPER1 is also
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investigated the side effects of triptans, which are widely upregulated during a migraine attack. Moreover, they
used as therapeutics for migraine but are often negatively revealed an increase in orofacial sensitivity in OVX female
accompanied with injection-site pain in patients. They rats with induced trigeminal inflammatory pain using the
showed significant sex-specific differences in the complex GPER1 agonist G-1. A study using a multibehavioral rat
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dose dependence for sumatriptan-induced mechanical model of migraine revealed an equivalent enhancement
hyperalgesia in male and female rats. Interestingly, of migraine-like behavior in female OVX rats through
1 ng of sumatriptan revealed hyperalgesia in male rats treatment with the xenoestrogen BPA. Moreover, they
implanted with estrogen and in female rats but not in reported an increase in the mRNA levels of ERa, GPER1,
untreated male rats or OVX female rats, highlighting ERK1/2, and Na 1.8 (SCN10A) in the trigeminal neurons
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the role of estrogen. Investigations on the responsible of BPA-treated rats, further suggesting a role of GPER1
ER revealed a significant involvement of GPER1 in in migraine and pain. Analysis of GPER1 involvement
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sumatriptan-induced mechanical hyperalgesia in female in OVX female rats with pre-operative anxiety-induced
rats. Moreover, the serotonin receptors 5-HT and post-operative hyperalgesia revealed a role of GPER1
1D
5-HT participate in sumatriptan-induced hyperalgesia, in this process, because the application of the GPER1
1B
while 5-HT is crucial in the induction of hyperalgesia in antagonist G-15 reduced post-operative hyperalgesia.
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1D
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female and 5-HT in male rats. Another study revealed Another study by Lu et al. demonstrated the opposite
1B
an important role of GPER1 in mechanical hyperalgesia, effect of GPER1 on pain induced by α, β-methylene ATP,
as high estrogen levels exacerbated postoperative activating the purinergic receptors P2X 1 and P2X 3 in
allodynia in OVX female rats through GPER1 and matrix OVX female rats. They showed that estrogen inhibited
metallopeptidase 9. Mechanical hyperalgesia increased the pain induced by α, β-methylene ATP, whereas an
with the use of the GPER1 agonist G-1 and equivalently ERα agonist and the GPER1 agonist G-1 mimicked the
decreased with the use of the GPER1 antagonist G-15, reduction in nociception, emphasizing a nocifensive role
emphasizing the role of GPER1 in vivo. However, in a of GPER1 in this context. At the molecular signaling level,
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mouse model of arthritis, the opposite effect of GPER1 cAMP-PKA and ERK1/2 play crucial roles in mediating
inhibition was observed, as biochanin treatment resulted the E2-based reduction in pain threshold. Regarding
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in decreased production of proinflammatory cytokines the epigenetic regulation of GPER1 or the impact of
and reduced hypernociception via GPER1. This is because nutraceuticals on GPER1 activity in the process of pain,
G-15 treatment reversed this positive effect in mice no specific data are available. Conclusively, there are
with antigen-induced arthritis. Accordingly, Liu and several studies confirming a relevant role of GPER1 in
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Duan investigated the role of progesterone in trigeminal modulating migraine-associated pain; however, the results
neurons of female rats and showed that progesterone- are controversial because some studies report an increase,
mediated neuroexcitation is dependent on cAMP and whereas others describe a decrease in nociception by
GPER1, because the application of the GPER1 antagonist GPER1 activation (Figure 1). These discrepancies may be
G-15 reversed the progesterone-induced enhancement in attributed to the different models used as well as the high
the excitability of Ah-type trigeminal neurons of female number of downstream signaling cascades activated by
rats. Conversely, a single application of the GPER1 GPER1.
agonist G-1 resulted in an increase in the action potential
frequency of Ah-type trigeminal neurons of female 2.8. Multiple sclerosis (MS)
rats. Investigations on two different mouse models of MS is a chronic inflammatory autoimmune disease of the
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pain, reflecting chronic inflammatory and neuropathic CNS, which is accompanied with inflammatory infiltration
pain, revealed anxiety-like behavior in OVX female mice and subsequent impairment of oligodendrocytes,
suffering from both types of pain, which was accompanied resulting in the destruction of myelin sheaths. Similar
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with high GPER1 expression in the basolateral amygdala. to the sex-specific prevalence of the previously discussed

Volume 4 Issue 1 (2025) 11 doi: 10.36922/gpd.4632