Oestrogen Increases Nociception Through ERK Activation in the Trigeminal Ganglion: Evidence for a Peripheral Mechanism of Allodynia

Abstract

The mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), is activated in experimental models of chronic pain, and is also activated by oestrogen. We used an established model of inflammatory trigeminal pain, injection of Complete Freund's Adjuvant (CFA) into the masseter muscle, to determine whether ERK activation may play a role in hormone-related trigeminal pain disorders. We measured withdrawal responses to stimulation of the masseter (V3, primary allodynia) and whisker pad (V2, secondary allodynia) using graded monofilaments. Oestrogen treatment in the presence of inflammation increased withdrawal response to stimulation of both masseter and whisker pad compared with inflammation alone, indicating an additive effect of inflammation and oestrogen on both primary and secondary allodynia. We examined ERK activation in trigeminal ganglia from each treatment group using western blot and immunohistochemistry. Both masseter inflammation and oestrogen treatment increased ERK activation, and combined treatment had an additive effect. Both masseter inflammation and oestrogen increased the percentage of pERK immunoreactive neurons in divisions 1 and 2 (V1/2), and combined treatment increased pERK immunoreactivity in V1/2 compared with inflammation alone. We stereotactically administered ERK antagonist U0126, or inactive control U0124, to the trigeminal ganglion of CFA+E2-treated rats. U0126 decreased withdrawal responses to mechanical stimulation of the whisker pad compared with U0124-treated rats. Because the secondary allodynia in V2 after inflammation in V3 was reduced by antagonizing ERK activation in the periphery, these data suggest a peripheral component to secondary allodynia mediated through ERK activation.

Behavioral effects and mechanisms of migraine pathogenesis following estradiol exposure in a multibehavioral model of migraine in rat

“…Trigeminal nucleus and ganglion, and dura mater tissue samples were isolated as previously described (Liverman, et al, 2009). Western blot analysis was performed for phosphorylated ERK (the activated form) using a 10% resolving SDS-PAGE gel and 5 micrograms of protein were loaded for each sample as previously described (Vermeer, 2014).…”

“…It is established that estradiol receptors are present in trigeminal nociceptors and studies have demonstrated that binding of estradiol leads to downstream activation of extracellular signal regulated kinase (ERK), a known inflammatory response pathway (Liverman, et al, 2009). Furthermore, it has been shown that estradiol exposure can lead to other nociceptive-related downstream effects; including, increased primary neuron activity (Cairns, et al, 2001, Cairns, et al, 2002), increased allodynia (Liverman, et al, 2009), altered sodium gated channel activity (Wang, et al, 2013), and enhanced vasodilation (Levy and Burstein, 2011, Sarajari and Oblinger, 2010).…”

17β-Estradiol Rapidly Enhances Bradykinin Signaling in Primary Sensory Neurons In Vitro and In Vivo

“…In DRG neurons in vitro, estrogen, acting via ER␣ associated with the plasma membrane, rapidly (with 5 min) reduces ATP-mediated intracellular calcium mobilization (Chaban and Micevych, 2005). Estrogen also rapidly activates extracellular signal-regulated kinase (Liverman et al, 2009) and interferes with exchange protein activated by cAMP-mediated activation of protein kinase Cε (Hucho et al, 2006). These data suggest that estrogen can exert multiple actions (genomic and nongenomic) on primary sensory neurons to regulate pain neurotransmission.…”

“…Estrogen receptors (ERs) are expressed in nociceptors of the trigeminal ganglia (TG) and dorsal root ganglia (DRG) (Yang et al, 1998;Bereiter et al, 2005), and treatment with 17␤-estradiol (17␤-E 2 ) influences a variety of functions and cellular processes in nociceptors such as expression of trkA mRNA (Liuzzi et al, 1999), expression of calcitonin generelated peptide mRNA and protein (Gangula et al, 2000), extracellular signal-regulated kinase activity (Liverman et al, 2009), calcium mobilization (Chaban and Micevych, 2005), and transient receptor potential cation channel V1 (TRPV1) function (Xu et al, 2008). Furthermore, local 17␤-E 2 injection into the temporomandibular joint reduces nociceptive behavioral responses to intrajoint administration of formalin (Fá varo-Moreira et al, 2009), suggesting estrogen's effect on nociceptors is functionally relevant.…”

Activation of Estrogen Receptor α Enhances Bradykinin Signaling in Peripheral Sensory Neurons of Female Rats

“…However, little is known about the contribution of these signaling pathways in mediating rapid effects of estrogen on nociception. In one study, rapid enhancement of inflammation-induced mechanical allodynia of the masseter muscle by estrogen was shown to be mediated by activation of extracellular signal-regulated kinase in sensory neurons (Liverman et al, 2009a). Additional experiments are needed to delineate the signaling pathway(s) regulated by membrane-associated ERa activation that mediates effects of estrogen to enhance BK-stimulated signaling in peripheral sensory neurons.…”