Understanding the endogenous processes that promote the activation and sensitization of meningeal nociceptors is important in explaining the mechanisms underlying migraine headache. The present findings provide direct evidence that IL-6 is important for sensitization of dural afferents by increasing neural excitability through modulation of Nav1.7. We also demonstrate that meningeal IL-6 application can produce migraine-like behavior through activation of the ERK pathway, supporting a role for IL-6 in migraine pathophysiology.
These studies demonstrate that direct meningeal application of exogenous IL-6 caused migraine-like behaviors in rats. However, the source of endogenous IL-6 during a migraine attack is not clear. Several lines of evidence have indicated that neurogenic inflammation underlies migraine headache pathogenesis with the involvement of at least 2 types of immune cells, dural mast cells and meningeal macrophages [29, 30]. The meninges are densely populated with mast cells, which reside in close proximity to afferent endings mostly within the dura compared to other meningeal layers [31–33]. A variety of well-known migraine precipitants, including stress (via the release of corticotrophin releasing hormone CRH or factor CRF) and CGRP trigger mast cell degranulation and the subsequent release of their inflammatory mediators . Relevant to the studies described here are reports that human mast cells can release IL-6 following stimulation [34, 35]. In addition to mast cells, IL-6 released from dural macrophages may also contribute to stress-induced neurogenic inflammation . Regardless of the source, IL-6 has the ability to sensitize nociceptors through actions on TRPV1 and ERK-mediated signaling to translation machinery [15, 36]. The experiments described here demonstrated that IL-6 application was able to sensitize identified dural afferents, and suggested additional mechanisms of IL-6 induced sensitization through phosphorylation of sodium channels.
Human genetic studies have demonstrated an important role for the sodium channel Nav1.7 in pain . Gain-of-function mutations of Nav1.7 are directly linked with several extreme pain conditions in humans such as erythromelalgia and paroxysmal extreme pain disorder, whereas loss-of-function mutation of Nav1.7 is associated with congenital insensitivity to pain . Although the gain-of-function mutations do not lead to headache and the location specific nature of the spontaneous pain in these disorders is poorly understood, these conditions highlight the importance of this channel in nociceptive signaling and suggest that sensitization of Nav1.7 may contribute to enhanced pain signaling from many areas including the head. Due to its distinctive slow development of closed-state inactivation, Nav1.7 is able to generate current in response to sub-threshold depolarization, thus playing an important role in amplifying excitatory inputs and modulating neuronal excitability . Additionally, inhibition of Nav1.7 is known to decrease neuronal excitability [38, 39]. Preclinical work has also indicated an important role for Nav1.7 in mediating inflammatory pain as supported by the evidence that formalin-induced mechanical allodynia and thermal hyperalgesia are abrogated in Nav1.7 knockout mice . Moreover, mRNA and protein levels of Nav1.7 increase following carrageenan injection, which parallel the increase in TTX-S currents . Hence, preclinical and clinical studies have created a compelling rationale for targeting Nav1.7 in inflammatory pain. The present work indicates that IL-6 application increases the number of spikes and decreases the latency to the first AP in response to ramp stimuli protocols, which are consistent with hyperexcitability induced by Nav1.7 phosphorylation . This IL-6-induced hyperexcitability is mediated through ERK signaling, which is similar to prior work showing that inhibition of ERK1/2 decreases excitability in DRG neurons . Additionally, and consistent with the previous study showing that pERK1, but not pERK2 phosphorylated the L1 loop of Nav1.7 , increased association between ERK1 and Nav1.7 was detected following IL-6 treatment, indicating that IL-6-activated signaling pathways are capable of modulating Nav1.7 directly. While we cannot rule out the possibility that modulation of other channels contributes to electrophysiological effects following IL-6 treatment, the findings reported here support the hypothesis that IL-6 produces sodium channel-dependent hyperexcitability and migraine-related behavior through activation of the ERK pathway.