Endoplasmic reticulum stress in the dorsal root ganglia regulates large‐conductance potassium channels and contributes to pain in a model of multiple sclerosis

Yousuf, Muhammad Saad; Samtleben, Samira; Lamothe, Shawn M.; Friedman, Timothy N.; Catuneanu, Ana; Thorburn, Kevin; Desai, Mansi; Tenorio, Gustavo; Schenk, Geert J.; Ballanyi, Klaus; Kurata, Harley T.; Simmen, Thomas; Kerr, Bradley J.

doi:10.1096/fj.202001163r

Cited by 27 publications

(23 citation statements)

References 68 publications

(172 reference statements)

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“… 5 Induction of eIF2α phosphorylation is known to promote pain in a number of pathological conditions associated with sensory neuropathy. 7 , 36 , 102 To our surprise, we noted that type I interferons did not induce an eIF2α-mediated response in nociceptors. Rather, we observed induction of mitogen-activated protein kinase–interacting kinase (MNK1/2)-mediated eIF4E phosphorylation, 6 a different pathway that promotes the synthesis of proteins from a subset of mRNAs that are associated with promoting pain.…”

Section: Neurobiology Of Virus-induced Painmentioning

confidence: 76%

Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain

McFarland

Yousuf

Shiers

et al. 2021

PR9

101

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SARS-CoV-2 is a novel coronavirus that infects cells through the angiotensin-converting enzyme 2 receptor, aided by proteases that prime the spike protein of the virus to enhance cellular entry. Neuropilin 1 and 2 (NRP1 and NRP2) act as additional viral entry factors. SARS-CoV-2 infection causes COVID-19 disease. There is now strong evidence for neurological impacts of COVID-19, with pain as an important symptom, both in the acute phase of the disease and at later stages that are colloquially referred to as "long COVID." In this narrative review, we discuss how COVID-19 may interact with the peripheral nervous system to cause pain in the early and late stages of the disease. We begin with a review of the state of the science on how viruses cause pain through direct and indirect interactions with nociceptors. We then cover what we currently know about how the unique cytokine profiles of moderate and severe COVID-19 may drive plasticity in nociceptors to promote pain and worsen existing pain states. Finally, we review evidence for direct infection of nociceptors by SARS-CoV-2 and the implications of this potential neurotropism. The state of the science points to multiple potential mechanisms through which COVID-19 could induce changes in nociceptor excitability that would be expected to promote pain, induce neuropathies, and worsen existing pain states.

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Section: Neurobiology Of Virus-induced Painmentioning

confidence: 76%

Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain

McFarland

Yousuf

Shiers

et al. 2021

PR9

101

View full text Add to dashboard Cite

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“…The calcium-sensitive large conductance K + channels (BK) have recently been implicated in pain mechanisms during EAE ( 195 ). These channels are found in DRG neurons of mice with EAE and play a role in the endoplasmic reticulum (ER) stress-mediated pain response.…”

Section: The Role Of Ion Channels Pumps and Exchangers In Neuropathic Pain: Evaluating The Potential Contribution To Pain In Eaementioning

confidence: 99%

“…These channels are found in DRG neurons of mice with EAE and play a role in the endoplasmic reticulum (ER) stress-mediated pain response. It has been hypothesized that the prolonged neuroinflammation that occurs in the CNS during MS/EAE affects DRG neurons by conveying retrograde stress signals, which, in turn, induce ER stress ( 195 ). In fact, ER stress markers are elevated in post-mortem DRG of individuals with MS.…”

Section: The Role Of Ion Channels Pumps and Exchangers In Neuropathic Pain: Evaluating The Potential Contribution To Pain In Eaementioning

confidence: 99%

Neuropathic Pain in Multiple Sclerosis and Its Animal Models: Focus on Mechanisms, Knowledge Gaps and Future Directions

Mirabelli

Elkabes

2021

Front. Neurol.

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Multiple sclerosis (MS) is a multifaceted, complex and chronic neurological disease that leads to motor, sensory and cognitive deficits. MS symptoms are unpredictable and exceedingly variable. Pain is a frequent symptom of MS and manifests as nociceptive or neuropathic pain, even at early disease stages. Neuropathic pain is one of the most debilitating symptoms that reduces quality of life and interferes with daily activities, particularly because conventional pharmacotherapies do not adequately alleviate neuropathic pain. Despite advances, the mechanisms underlying neuropathic pain in MS remain elusive. The majority of the studies investigating the pathophysiology of MS-associated neuropathic pain have been performed in animal models that replicate some of the clinical and neuropathological features of MS. Experimental autoimmune encephalomyelitis (EAE) is one of the best-characterized and most commonly used animal models of MS. As in the case of individuals with MS, rodents affected by EAE manifest increased sensitivity to pain which can be assessed by well-established assays. Investigations on EAE provided valuable insights into the pathophysiology of neuropathic pain. Nevertheless, additional investigations are warranted to better understand the events that lead to the onset and maintenance of neuropathic pain in order to identify targets that can facilitate the development of more effective therapeutic interventions. The goal of the present review is to provide an overview of several mechanisms implicated in neuropathic pain in EAE by summarizing published reports. We discuss current knowledge gaps and future research directions, especially based on information obtained by use of other animal models of neuropathic pain such as nerve injury.

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“…It has also been suggested that endoplasmic reticulum stress associated with nerve injury may contribute to pain by alteration of BK function (Yousuf et al, 2020).…”

Section: Distribution Of Intermediate Conductance K Ca Channels (K Camentioning

confidence: 99%

K+ Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain

Smith

2020

Front. Cell. Neurosci.

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Sensory abnormalities generated by nerve injury, peripheral neuropathy or disease are often expressed as neuropathic pain. This type of pain is frequently resistant to therapeutic intervention and may be intractable. Numerous studies have revealed the importance of enduring increases in primary afferent excitability and persistent spontaneous activity in the onset and maintenance of peripherally induced neuropathic pain. Some of this activity results from modulation, increased activity and /or expression of voltage-gated Na + channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. K + channels expressed in dorsal root ganglia (DRG) include delayed rectifiers (K v 1.1, 1.2), A-channels (K v 1.4, 3.3, 3.4, 4.1, 4.2, and 4.3), KCNQ or M-channels (K v 7.2, 7.3, 7.4, and 7.5), ATP-sensitive channels (K IR 6.2), Ca 2+-activated K + channels (K Ca 1.1, 2.1, 2.2, 2.3, and 3.1), Na +-activated K + channels (K Ca 4.1 and 4.2) and two pore domain leak channels (K 2p ; TWIK related channels). Function of all K + channel types is reduced via a multiplicity of processes leading to altered expression and/or post-translational modification. This also increases excitability of DRG cell bodies and nociceptive free nerve endings, alters axonal conduction and increases neurotransmitter release from primary afferent terminals in the spinal dorsal horn. Correlation of these cellular changes with behavioral studies provides almost indisputable evidence for K + channel dysfunction in the onset and maintenance of neuropathic pain. This idea is underlined by the observation that selective impairment of just one subtype of DRG K + channel can produce signs of pain in vivo. Whilst it is established that various mediators, including cytokines and growth factors bring about injury-induced changes in DRG function and excitability, evidence presently available points to a seminal role for interleukin 1β (IL-1β) in control of K + channel function. Despite the current state of knowledge, attempts to target K + channels for therapeutic pain management have met with limited success. This situation may change with the advent of personalized medicine. Identification of specific sensory abnormalities and genetic profiling of individual patients may predict therapeutic benefit of K + channel activators.

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Endoplasmic reticulum stress in the dorsal root ganglia regulates large‐conductance potassium channels and contributes to pain in a model of multiple sclerosis

Cited by 27 publications

References 68 publications

Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain

Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain

Neuropathic Pain in Multiple Sclerosis and Its Animal Models: Focus on Mechanisms, Knowledge Gaps and Future Directions

K+ Channels in Primary Afferents and Their Role in Nerve Injury-Induced Pain

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