Peripheral sensory neuron injury contributes to neuropathic pain in experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS)-induced neuropathic pain deteriorates quality of life in patients but is often refractory to treatment. In experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, animals develop neuropathy and inflammation-induced tissue acidosis, which suggests the involvement of acid-sensing ion channels (ASICs). Also, peripheral neuropathy is reported in MS patients. However, the involvement of the peripheral nervous system (PNS) in MS neuropathic pain remains elusive. This study investigated the contribution of ASICs and peripheral neuropathy in MS-induced neuropathic pain. Elicited pain levels were as high in Asic1a−/−, Asic2−/− and Asic3−/− mice as wild-type mice even though only Asic1a−/− mice showed reduced EAE disease severity, which indicates that pain in EAE was independent of disease severity. We thus adopted an EAE model without pertussis toxin (EAEnp) to restrain activated immunity in the periphery and evaluate the PNS contribution to pain. Both EAE and EAEnp mice showed similar pain behaviors and peripheral neuropathy in nerve fibers and DRG neurons. Moreover, pregabalin significantly reduced neuropathic pain in both EAE and EAEnp mice. Our findings highlight the essential role of the PNS in neuropathic pain in EAE and pave the way for future development of analgesics without side effects in the CNS.

Regulatory T Cells and Their Derived Cytokine, Interleukin-35, Reduce Pain in Experimental Autoimmune Encephalomyelitis

“…despite no change in clinical EAE. Similar to other EAE studies (Duffy et al, 2016;Frezel et al, 2016;Wang et al, 2017), our findings further support the idea that pain behaviors are independent of clinical severity in EAE. Additionally, our results are consistent with a previous report demonstrating that intrathecal injection of CD4 ϩ CD25 ϩ Treg cells relieves mechanical allodynia in mice treated with the chemotherapeutic paclitaxel (Liu et al, 2014).…”

Involvement of advillin in somatosensory neuron subtype-specific axon regeneration and neuropathic pain

“…We hypothesized that in the context of peripheral neuropathy, advillin would be detectable in cerebrospinal fluid (CSF) if advillin-associated nascent focal adhesions are shed during active neurite retraction accompanied by axonal regeneration. We analyzed the CSF of naïve mice and EAE mice, a mouse model of multiple sclerosis that shows severe peripheral neuropathy associated with IB4 + sensory neurons ( 23 ). Advillin and myosin IIa protein was detectable in the CSF of EAE mice in the recovery phase, defined as after day 30 in the EAE model, with score 3 or higher, but was not detectable in naïve healthy mice ( Fig.…”

“…IB4 + DRG neurons belong to the nonpeptidergic nociceptors that are largely involved in pain associated with peripheral neuropathy induced by chemotherapy, chronic constriction, and EAE ( 23 , 35 , 36 ). For example, nerve injury-induced mechanical allodynia is significantly reduced when IB4-binding afferent neurons are specifically deleted by the toxin saporin ( 37 ).…”

“…Here, we used immunostaining, live imaging, biochemistry, and genetic approaches to examine the expression of advillin in axonal growth cones, the key structure that determines the destiny of neurite outgrowth. Then, we probed the roles of advillin in the context of nerve regeneration and neuropathic pain in: ( i ) a mouse model of multiple sclerosis induced by experimental autoimmune encephalomyelitis (EAE), a demyelinating autoimmune disease accompanied by severe sensory neuropathy ( 22 , 23 ); ( ii ) a peripheral neuropathy model induced by oxaliplatin, a drug used to treat colorectal cancer ( 24 ); and ( iii ) a localized nerve lesion model induced by chronic constriction injury (CCI) of the sciatic nerve ( 25 , 26 ).…”

Anti-IL-6 receptor antibody improves pain symptoms in mice with experimental autoimmune encephalomyelitis

“…Peripheral IL-6 increases TRPV-1 expression in dorsal root ganglion neurons and causes sensitization of unmyelinated sensory fibers, leading to various types of pathological pain (Brenn et al, 2007;Fang et al, 2015). It has been recently reported that myelin disruption and injured neurons are observed in the peripheral nervous system of EAE mice, suggesting that peripheral neuropathy is involved in EAEinduced neuropathic pain (Wang et al, 2017). In contrast, Olechowski et al indicated that sensory neuropeptides such as calcitonin gene-related peptide and galanin were not changed in EAE mice (Olechowski et al, 2009).…”