Activation of Lumbar Spinal Wide-Dynamic Range Neurons by a Sanshool Derivative

Sawyer, Carolyn M.; Carstens, Mirela Iodi; Simons, Christopher T.; Slack, Jay P.; McCluskey, T. Scott; Furrer, Stefan; Carstens, Earl

doi:10.1152/jn.91311.2008

Cited by 17 publications

(23 citation statements)

References 27 publications

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“…IBA, an alkylamide derivative [25,38] was first tested on HEK293 cells co-transfected with rat TRESK and eGFP to verify its blocking activity on this channel. 100 μM IBA application blocked total background current by 19.6 ± 3.3% (p < 0.01; n = 6) and 69.5 ± 8.7% at 500 μM (p < 0.001; n = 7; Figure 4A, B), which returned to basal values after washing the drug.…”

Section: Resultsmentioning

confidence: 99%

TRESK Channel Contribution to Nociceptive Sensory Neurons Excitability: Modulation by Nerve Injury

Cokić²,

et al. 2011

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BackgroundNeuronal hyperexcitability is a crucial phenomenon underlying spontaneous and evoked pain. In invertebrate nociceptors, the S-type leak K+ channel (analogous to TREK-1 in mammals) plays a critical role of in determining neuronal excitability following nerve injury. Few data are available on the role of leak K2P channels after peripheral axotomy in mammals.ResultsHere we describe that rat sciatic nerve axotomy induces hyperexcitability of L4-L5 DRG sensory neurons and decreases TRESK (K2P18.1) expression, a channel with a major contribution to total leak current in DRGs. While the expression of other channels from the same family did not significantly change, injury markers ATF3 and Cacna2d1 were highly upregulated. Similarly, acute sensory neuron dissociation (in vitro axotomy) produced marked hyperexcitability and similar total background currents compared with neurons injured in vivo. In addition, the sanshool derivative IBA, which blocked TRESK currents in transfected HEK293 cells and DRGs, increased intracellular calcium in 49% of DRG neurons in culture. Most IBA-responding neurons (71%) also responded to the TRPV1 agonist capsaicin, indicating that they were nociceptors. Additional evidence of a biological role of TRESK channels was provided by behavioral evidence of pain (flinching and licking), in vivo electrophysiological evidence of C-nociceptor activation following IBA injection in the rat hindpaw, and increased sensitivity to painful pressure after TRESK knockdown in vivo.ConclusionsIn summary, our results clearly support an important role of TRESK channels in determining neuronal excitability in specific DRG neurons subpopulations, and show that axonal injury down-regulates TRESK channels, therefore contributing to neuronal hyperexcitability.

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Section: Resultsmentioning

confidence: 99%

TRESK Channel Contribution to Nociceptive Sensory Neurons Excitability: Modulation by Nerve Injury

Cokić²,

et al. 2011

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“…Intraplantar IBA in rats elicited nocifensive behaviors (flinching, guarding, licking) (Klein et al 2011b) and excited both nociceptive and nonnociceptive spinal dorsal horn neurons (Sawyer et al 2009). We speculate that the tingle sensation elicited by IBA is novel and hence aversive, but not painful, resulting in the observed range of nocifensive responses that are available to the animal to respond to unusual sensations.…”

Section: Discussionmentioning

confidence: 99%

“…Itch is a symptom common to many skin and systemic disorders and is usually resistant to treatment, thus representing a significant health issue (Carstens 2009). It is therefore important to better understand itch mechanisms under normal and pathophysiological conditions, an effort that benefits greatly from animal models.…”

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confidence: 99%

Facial injections of pruritogens or algogens elicit distinct behavior responses in rats and excite overlapping populations of primary sensory and trigeminal subnucleus caudalis neurons

Klein

Carstens

2011

Journal of Neurophysiology

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Klein A, Carstens MI, Carstens E. Facial injections of pruritogens or algogens elicit distinct behavior responses in rats and excite overlapping populations of primary sensory and trigeminal subnucleus caudalis neurons. J Neurophysiol 106: 1078 -1088. First published June 8, 2011 doi:10.1152/jn.00302.2011In the present study, we investigated whether intradermal cheek injection of pruritogens or algogens differentially elicits hindlimb scratches or forelimb wipes in Sprague-Dawley rats, as recently reported in mice. We also investigated responses of primary sensory trigeminal ganglion (TG) and dorsal root ganglion (DRG) cells, as well as second-order neurons in trigeminal subnucleus caudalis (Vc), to pruritic and algesic stimuli. 5-HT was the most effective chemical to elicit dose-dependent bouts of hindlimb scratches directed to the cheek, with significantly less forelimb wiping, consistent with itch. Chloroquine also elicited significant scratching but not wiping. Allyl isothiocyanate (AITC; mustard oil) elicited dose-dependent wiping with no significant scratching. Capsaicin elicited equivalent numbers of scratch bouts and wipes, suggesting a mixed itch and pain sensation. By calcium imaging, ϳ6% of cultured TG and DRG cells responded to 5-HT. The majority of 5-HT-sensitive cells also responded to chloroquine, AITC, and/or capsaicin, and one-third responded to histamine. Using a chemical search strategy, we identified single units in Vc that responded to intradermal cheek injection of 5-HT. Most were wide dynamic range (WDR) or nociceptive specific (NS), and a few were mechanically insensitive. The large majority additionally responded to AITC and/or capsaicin and thus were not pruritogen selective. These results suggest that primary and second-order neurons responsive to pruritogens and algogens may utilize a population coding mechanism to distinguish between itch and pain, sensations that are behaviorally manifested by distinct hindlimb scratching and forelimb wiping responses.

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“…However, these authors propose that the compound acts on a distinct subset of primary afferent capsaicin-sensitive, mustard oil-insensitive sensory neurons, which may not be involved in pain sensation [58]. Similarly, the synthetic alkylamide IBA activates certain spinal neurons that receive convergent input from mechanoreceptors and nociceptors [89], and there is in vivo electrophysiological evidence of C-nociceptor activation following IBA injection in the rat hindpaw [98].…”

Section: Tresk Channelsmentioning

confidence: 99%

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Mathie

Veale

2014

Pflugers Arch - Eur J Physiol

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Recent evidence points to a pivotal contribution of a variety of different potassium channels, including two-pore domain potassium (K2P) channels, in chronic pain processing. Expression of several different K2P channel subunits has been detected in nociceptive dorsal root ganglion neurons and trigeminal ganglion neurons, in particular, TREK1, TREK2, TRESK, TRAAK, TASK3 and TWIK1 channels. Of these, the strongest body of evidence from functional studies highlights the importance of TREK1, TRESK and, recently, TREK2 channels. For example, TREK1 knockout mice are more sensitive than wild-type mice to a number of painful stimuli but less sensitive to morphine-induced analgesia. TRESK knockdown mice show behavioural evidence of increased pain and increased sensitivity to painful pressure. Importantly, familial migraine with aura is associated with a dominant-negative mutation in human TRESK channels. Thus, the functional up-regulation of K2P channel activity may be a useful strategy in the development of new therapies for the treatment of pain. Whilst there are few currently available compounds that selectively and directly enhance the activity of TRESK and TREK2 channels, recent advances have been made in terms of identifying compounds that activate TREK1 channels and in understanding how they might act on the channel. Large-scale bio-informatic approaches and the further development of databases of putative ligands, channel structures and putative ligand binding sites on these structures may form the basis for future experimental strategies to detect novel molecules acting to enhance K2P channel activity that would be useful in the treatment of pain.

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Activation of Lumbar Spinal Wide-Dynamic Range Neurons by a Sanshool Derivative

Cited by 17 publications

References 27 publications

TRESK Channel Contribution to Nociceptive Sensory Neurons Excitability: Modulation by Nerve Injury

TRESK Channel Contribution to Nociceptive Sensory Neurons Excitability: Modulation by Nerve Injury

Facial injections of pruritogens or algogens elicit distinct behavior responses in rats and excite overlapping populations of primary sensory and trigeminal subnucleus caudalis neurons

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

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