The Use of Inhibitors of Mechanosensitive Ion Channels as Local Inhibitors of Peripheral Pain

Sachs, Frederick

doi:10.21236/ada611580

Cited by 3 publications

(4 citation statements)

References 5 publications

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“…However, these studies used gadolinium, a nonselective mechano-gated inhibitor, to block the mechanoreflex during muscle contraction in cats (26,27). We chose to use GsMTx-4, as it is a more selective mechanogated inhibitor than gadolinium and has been shown to inhibit both Piezo1 and Piezo2 channels (4,51). The Piezo protein family, including Piezo1 and Piezo2 channels, comprises rapidly adapting stretch-activated cation channels.…”

Section: Discussionmentioning

confidence: 99%

“…Although this study clearly suggests a role for Piezo channels in the exaggerated mechanoreflex in T1DM rats, it is possible that other mechanically sensitive channels and/or metabolite-induced sensitization of these channels also play a role in evoking the exaggerated mechanoreflex. GsMTx-4 inhibits cationic mechanosensitive channels by forcing them into a closed state with high potency for Piezo and transient receptor potential (TRP) channel families (11,51,54). Specifically, intradermal injection of GsMTx-4 into the rat hindpaw reversed inflammation-induced mechanical hyperalgesia, possibly via decreased sensitization of C-fibers, by inhibiting stretch-activated TRPC1 and TRPC6 channels (2).…”

Section: Discussionmentioning

confidence: 99%

“…Because gadolinium has been found to inhibit multiple classes of mechano-gated channels (15,24,41), the mechanism of action is not clear. More recently, GsMTx-4, which originates from the toxin of the tarantula spider Grammostola spatulata, has been used as a selective inhibitor of Piezo1 and Piezo2 mechano-gated cation channels (15,51). While Piezo1 channels are found mainly in epithelial cells, Piezo2 channels are found in sensory neurons and play an important role in sensing touch and evoking pain (48).…”

Section: Introductionmentioning

confidence: 99%

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Exaggerated mechanoreflex in early-stage type 1 diabetic rats: role of Piezo channels

Grotle

García

Harrison

et al. 2019

American Journal of Physiology-Regulatory, Integrative and Comp

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Recent findings have shown that muscle contraction evokes an exaggerated pressor response in type 1 diabetes mellitus (T1DM) rats; however, it is not known whether the mechanoreflex, which is commonly stimulated by stretching the Achilles tendon, contributes to this abnormal response. Furthermore, the role of mechano-gated Piezo channels, found on thin-fiber afferent endings, in evoking the mechanoreflex in T1DM is also unknown. Therefore, in male and female streptozotocin (STZ, 50 mg/kg)-induced T1DM and healthy control (CTL) rats, we examined the pressor and cardioaccelerator responses to tendon stretch during the early stage of the disease. To determine the role of Piezo channels, GsMTx-4, a selective Piezo channel inhibitor, was injected into the arterial supply of the hindlimb. At 1 wk after STZ injection in unanesthetized, decerebrate rats, we stretched the Achilles tendon for 30 s and measured pressor and cardioaccelerator responses. We then compared pressor and cardioaccelerator responses to tendon stretch before and after GsMTx-4 injection (10 µg/100 ml). We found that the pressor (change in mean arterial pressure) response [41 ± 5 mmHg ( n = 15) for STZ and 18 ± 3 mmHg ( n = 11) for CTL ( P < 0.01)] and cardioaccelerator (change in heart rate) response [18 ± 4 beats/min for STZ ( n = 15) and 8 ± 2 beats/min ( n = 11) for CTL ( P < 0.05)] to tendon stretch were exaggerated in STZ rats. Local injection of GsMTx-4 attenuated the pressor [55 ± 7 mmHg ( n = 6) before and 27 ± 9 mmHg ( n = 6) after GsMTx-4 ( P < 0.01)], but not the cardioaccelerator, response to tendon stretch in STZ rats and had no effect on either response in CTL rats. These data suggest that T1DM exaggerates the mechanoreflex response to tendon stretch and that Piezo channels play a role in this exaggeration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Exaggerated mechanoreflex in early-stage type 1 diabetic rats: role of Piezo channels

Grotle

García

Harrison

et al. 2019

American Journal of Physiology-Regulatory, Integrative and Comp

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“…GsMTx4 inhibits these channels by inserting into the lipid bilayer at the channel-membrane interface and "pushing" the channel to a closed state (43). Importantly, GsMTx4 inhibits both Piezo1 (4,5,26) and Piezo2 (33), with at least some selectivity for Piezo channels because it did not inhibit mechano-gated TREK-1 channels (5). Our finding that 10 g of GsMTx4 did not inhibit metabolically sensitive receptors in the present study is important because GsMTx4 has been reported to exert off-target effects.…”

Section: Discussionmentioning

confidence: 99%

The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in rats with ligated femoral arteries

Copp

Kim

Ruiz‐Velasco

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Mechanical and metabolic stimuli arising from contracting muscles evoke the exercise pressor reflex. This reflex is greater in a rat model of simulated peripheral arterial disease in which a femoral artery is chronically ligated than it is in rats with freely perfused femoral arteries. The role played by the mechanically sensitive component of the exaggerated exercise pressor reflex in ligated rats is unknown. We tested the hypothesis that the mechano-gated channel inhibitor GsMTx4, a relatively selective inhibitor of mechano-gated Piezo channels, reduces the exercise pressor reflex in decerebrate rats with ligated femoral arteries. Injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb reduced the pressor response to Achilles tendon stretch (a purely mechanical stimulus) but had no effect on the pressor responses to intra-arterial injection of α,β-methylene ATP or lactic acid (purely metabolic stimuli). Moreover, injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb reduced both the integrated pressor area (control 535 ± 21, GsMTx4 218 ± 24 mmHg·s; P < 0.01), peak pressor (control 29 ± 2, GsMTx4 14 ± 3 mmHg; P < 0.01), and renal sympathetic nerve responses to electrically induced intermittent hindlimb muscle contraction (a mixed mechanical and metabolic stimulus). The reduction of the integrated pressor area during contraction caused by GsMTx4 was greater in rats with ligated femoral arteries than it was in rats with freely perfused femoral arteries. We conclude that the mechanically sensitive component of the reflex contributes to the exaggerated exercise pressor reflex during intermittent hindlimb muscle contractions in rats with ligated femoral arteries.

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The mechano‐gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats

Copp

Kim

Ruiz‐Velasco

et al. 2016

The Journal of Physiology

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Key pointsr Mechanical and metabolic stimuli from contracting muscles evoke reflex increases in blood pressure, heart rate and sympathetic nerve activity. Little is known, however, about the nature of the mechano-gated channels on the thin fibre muscle afferents that contribute to evoke this reflex, termed the exercise pressor reflex.r We determined the effect of GsMTx4, an inhibitor of mechano-gated Piezo channels, on the exercise pressor reflex evoked by intermittent contraction of the triceps surae muscles in decerebrated, unanaesthetized rats.r GsMTx4 reduced the pressor, cardioaccelerator and renal sympathetic nerve responses to intermittent contraction but did not reduce the pressor responses to femoral arterial injection of compounds that stimulate the metabolically-sensitive thin fibre muscle afferents.r Expression levels of Piezo2 channels were greater than Piezo1 channels in rat dorsal root ganglia.r Our findings suggest that mechanically-sensitive Piezo proteins contribute to the generation of the mechanical component of the exercise pressor reflex in rats.Abstract Mechanical and metabolic stimuli within contracting skeletal muscles evoke reflex autonomic and cardiovascular adjustments. In cats and rats, gadolinium has been used to investigate the role played by the mechanical component of this reflex, termed the exercise pressor reflex. Gadolinium, however, has poor selectivity for mechano-gated channels and exerts multiple off-target effects. We tested the hypothesis that GsMTX4, a more selective mechano-gated channel inhibitor than gadolinium and a particularly potent inhibitor of mechano-gated Piezo channels, reduced the exercise pressor reflex in decerebrate rats. Injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb reduced the peak pressor (control: 24 ± 5, GsMTx4: 12 ± 5 mmHg, P < 0.01), cardioaccelerator and renal sympathetic nerve responses to tendon stretch, a purely mechanical stimulus, but had no effect on the pressor responses to intra-arterial injection of α,β-methylene ATP or lactic acid. Moreover, injection of 10 μg of GsMTx4 into the arterial supply of the hindlimb reduced the peak pressor (control: 24 ± 2, GsMTx4: 14 ± 3 mmHg, P < 0.01), cardioaccelerator and renal sympathetic nerve responses to electrically-induced intermittent hindlimb muscle contractions. By contrast, injection of 10 μg of GsMTx4 into the jugular vein had no effect on the pressor, cardioaccelerator, or renal sympathetic nerve responses to contraction. Quantitative RT-PCR and western blot analyses indicated that both Piezo1 and Piezo2 channel isoforms were natively expressed in rat dorsal root ganglia tissue. We conclude that GsMTx4 reduced the exercise pressor reflex in decerebrate rats and that the reduction was attributable, at least in part, to its effect on mechano-gated Piezo channels.

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The Use of Inhibitors of Mechanosensitive Ion Channels as Local Inhibitors of Peripheral Pain

Cited by 3 publications

References 5 publications

Exaggerated mechanoreflex in early-stage type 1 diabetic rats: role of Piezo channels

Exaggerated mechanoreflex in early-stage type 1 diabetic rats: role of Piezo channels

The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in rats with ligated femoral arteries

The mechano‐gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats

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