Role of Kv4.3 in Vibration-Induced Muscle Pain in the Rat

Conner, Lindsay B.; Álvarez, Pedro; Bogen, Oliver; Levine, Jon D.

doi:10.1016/j.jpain.2015.12.007

Cited by 20 publications

(22 citation statements)

References 57 publications

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“…Nevertheless, in our present study, HpTx3 used in several pain models showed potent analgesic activity, suggesting that the analgesic effect of HpTx3 overwhelmed the hyperalgesia it caused. This result may be explained at least partially by the fact that in the pain models the level of K v 4 channels is usually decreased [56,61,64,65]. Till now, only one model showed that the expression of K v 4 channels was increased following injury [58].…”

Section: Discussionmentioning

confidence: 99%

Newly Discovered Action of HpTx3 from Venom of Heteropoda venatoria on Nav1.7 and Its Pharmacological Implications in Analgesia

Wang

Chen

et al. 2019

Toxins

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It has been reported that Heteropodatoxin3 (HpTx3), a peptidic neurotoxin purified from the venom of the spider species Heteropoda venatoria, could inhibit Kv4.2 channels. Our present study newly found that HpTx3 also has potent and selective inhibitory action on Nav1.7, with an IC50 of 135.61 ± 12.98 nM. Without effect on the current–voltage (I-V) relationship of Nav1.7, HpTx3 made minor alternation in the voltage-dependence of activation and steady-state inactivation of Nav1.7 (4.15 mV and 7.29 mV, respectively) by interacting with the extracellular S3–S4 loop (S3b–S4 sequence) in domain II and the domain IV of the Nav channel subtype, showing the characteristics of both pore blocker and gate modifier toxin. During the interaction of HpTx3 with the S3b–S4 sequence of Nav1.7, the amino acid residue D in the sequence played a key role. When administered intraperitoneally or intramuscularly, HpTx3 displayed potent analgesic activity in a dose-dependent manner in different mouse pain models induced by formalin, acetic acid, complete Freund’s adjuvant, hot plate, or spared nerve injury, demonstrating that acute, inflammatory, and neuropathic pains were all effectively inhibited by the toxin. In most cases HpTx3 at doses of ≥ 1mg/kg could produce the analgesic effect comparable to that of 1 mg/kg morphine. These results suggest that HpTx3 not only can be used as a molecular probe to investigate ion channel function and pain mechanism, but also has potential in the development of the drugs that treat the Nav1.7 channel-related pain.

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Section: Discussionmentioning

confidence: 99%

Newly Discovered Action of HpTx3 from Venom of Heteropoda venatoria on Nav1.7 and Its Pharmacological Implications in Analgesia

Wang

Chen

et al. 2019

Toxins

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“…injection of antisense (AS) oligodeoxynucleotides (ODN) directed against IL-10R1 mRNA. This approach has been shown to produce a reversible inhibition of the expression of several proteins involved in pain processing in DRG neurons (for a review see [49]) and to modulate a number of behavioral nociceptive responses, including mechanical hyperalgesia in skeletal muscle [2–4,13,17]. The AS ODN sequence, 5′-TTG TCC CGT AGA TGA AGC CGT TGC-3′, was directed against a unique sequence in rat IL-10R1 mRNA.…”

Section: Methodsmentioning

confidence: 99%

“…Changes in IL-10R1 expression in lumbar DRGs were evaluated by Western blot analysis as previously described [13]. Briefly, rats were euthanized by exsanguination, while under deep isoflurane anesthesia, 24 h after the last i.t.…”

Section: Methodsmentioning

confidence: 99%

Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat

Álvarez

Bogen

Green

et al. 2017

PAIN

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Delayed-onset muscle soreness is typically observed after strenuous or unaccustomed eccentric exercise. Soon after recovery, blunted muscle soreness is observed on repeated eccentric exercise, a phenomenon known as repeated bout effect (RBE). Although regular physical activity decreases muscle hyperalgesia, likely because of increased production of the anti-inflammatory cytokine interleukin-10 (IL-10) in the skeletal muscle, whether IL-10 also contributes to the antinociceptive effect of RBE is unknown. Furthermore, whether IL-10 attenuates muscle hyperalgesia by acting on muscle nociceptors remains to be established. Here, we explored the hypothesis that blunted muscle nociception observed in RBE depends on a local effect of IL-10, acting on IL-10 receptor 1 (IL-10R1) expressed by muscle nociceptors. Results show that after a second bout of eccentric exercise, rats exhibited decreased muscle hyperalgesia, indicative of RBE, and increased expression of IL-10 in the exercised gastrocnemius muscle. Although knockdown of IL-10R1 protein in nociceptors innervating the gastrocnemius muscle by intrathecal antisense oligodeoxynucleotide did not change nociceptive threshold in naive rats, it unveiled latent muscle hyperalgesia in rats submitted to eccentric exercise 12 days ago. Furthermore, antisense also prevented the reduction of muscle hyperalgesia observed after a second bout of eccentric exercise. These data indicate that recovery of nociceptive threshold after eccentric exercise and RBE-induced analgesia depend on a local effect of IL-10, acting on its canonical receptor in muscle nociceptors.

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“…Subsequent studies showed that Kv4.3 DRG immunoreactivity is reduced by 40% following nerve ligation (Chien et al, 2007 ). Vibration induced injury decreases Kv4.3 mRNA in the nerves innervating the affected side (Conner et al, 2016 ). In streptozotocin (STZ)-induced diabetic neuropathy, there are robust decreases in A-type Kv currents and Kv4 expression in putative nociceptors after disease onset (Cao et al, 2010 ; Grabauskas et al, 2011 ; Sun et al, 2011 ).…”

Section: Function and Dysfunction Of A-type Kv Channel Subtypes In Drmentioning

confidence: 99%

“…Three days of intrathecal administration of Kv4.3 antisense oligonucleotides induces mechanical allodynia but not thermal hyperalgesia (Chien et al, 2007 ). A separate group also injected Kv4.3 channel antisense oligonucleotides and have shown increased sensitization to vibration (Conner et al, 2016 ). In a bone cancer model of chronic pain, injection of Kv4.3 siRNA in the lumbar spinal cord prohibits the ability of diclofenac to reverse the mechanical allodynia phenotype with no effect on thermal hyperalgesia (Duan et al, 2012 ).…”

Section: Function and Dysfunction Of A-type Kv Channel Subtypes In Drmentioning

confidence: 99%

A-Type KV Channels in Dorsal Root Ganglion Neurons: Diversity, Function, and Dysfunction

Zemel

Ritter

Covarrubias

et al. 2018

Front. Mol. Neurosci.

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A-type voltage-gated potassium (Kv) channels are major regulators of neuronal excitability that have been mainly characterized in the central nervous system. By contrast, there is a paucity of knowledge about the molecular physiology of these Kv channels in the peripheral nervous system, including highly specialized and heterogenous dorsal root ganglion (DRG) neurons. Although all A-type Kv channels display pore-forming subunits with similar structural properties and fast inactivation, their voltage-, and time-dependent properties and modulation are significantly different. These differences ultimately determine distinct physiological roles of diverse A-type Kv channels, and how their dysfunction might contribute to neurological disorders. The importance of A-type Kv channels in DRG neurons is highlighted by recent studies that have linked their dysfunction to persistent pain sensitization. Here, we review the molecular neurophysiology of A-type Kv channels with an emphasis on those that have been identified and investigated in DRG nociceptors (Kv1.4, Kv3.4, and Kv4s). Also, we discuss evidence implicating these Kv channels in neuropathic pain resulting from injury, and present a perspective of outstanding challenges that must be tackled in order to discover novel treatments for intractable pain disorders.

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Role of Kv4.3 in Vibration-Induced Muscle Pain in the Rat

Cited by 20 publications

References 57 publications

Newly Discovered Action of HpTx3 from Venom of Heteropoda venatoria on Nav1.7 and Its Pharmacological Implications in Analgesia

Newly Discovered Action of HpTx3 from Venom of Heteropoda venatoria on Nav1.7 and Its Pharmacological Implications in Analgesia

Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat

A-Type KV Channels in Dorsal Root Ganglion Neurons: Diversity, Function, and Dysfunction

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