Antitussive effects of NaV 1.7 blockade in Guinea pigs

Yu, Li; Tsuji, Kojun; Ujihara, Izumi; Liu, Qi; Pavelková, Nikoleta; Tsujimura, Takanori; Inoue, Makoto; Meeker, Sonya; Nisenbaum, Eric S.; McDermott, Jeff S.; Krajewski, Jeff; Undem, Bradley J.; Kollárik, Marián; Canning, Brendan J.

doi:10.1016/j.ejphar.2021.174192

Cited by 8 publications

(3 citation statements)

References 46 publications

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“…Most previous studies used the guinea pig as an animal model in monitoring cough reflexes ( Driessen et al., 2020 ; Ruhl et al., 2020 ; Yu et al., 2021 ). However, many new useful tools, such as pharmacogenetics, optogenetics, and fiber photometry, are difficult to use on guinea pigs owing to the lack of transgenic guinea pig models expressing cell type-specific Cre-recombinase.…”

Section: Resultsmentioning

confidence: 99%

A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity

et al. 2022

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Summary Chronic cough is a common refractory symptom of various respiratory diseases. However, the neural mechanisms that modulate the cough sensitivity and mediate chronic cough remain elusive. Here, we report that GABAergic neurons in the lateral/ventrolateral periaqueductal gray (l/vlPAG) suppress cough processing via a descending pathway. We found that l/vlPAG neurons are activated by coughing-like behaviors and that tussive agent-evoked coughing-like behaviors are impaired after activation of l/vlPAG neurons. In addition, we showed that l/vlPAG neurons form inhibitory synapses with the nucleus of the solitary tract (NTS) neurons. The synaptic strength of these inhibitory projections is weaker in cough hypersensitivity model mice than in naïve mice. Important, activation of l/vlPAG GABAergic neurons projecting to the NTS decreases coughing-like behaviors. In contrast, suppressing these neurons enhances cough sensitivity. These results support the notion that l/vlPAG GABAergic neurons play important roles in cough hypersensitivity and chronic cough through disinhibition of cough processing at the medullary level.

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Section: Resultsmentioning

confidence: 99%

A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity

et al. 2022

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“…These findings collectively suggest that an effective Na V 1.7 blocker could potentially lead to hypotensive effects. This prediction has recently been validated in guinea‐pigs and rats, where a relatively selective Na V 1.7 blocker was associated with decreases in blood pressure (Stone et al., 2015; Yu et al., 2021). Moreover, larger doses of a selective Na V 1.7 blocker have been associated with hypotensive responses in a human safety and tolerability trial (Rothenberg et al., 2019).…”

Section: Discussionmentioning

confidence: 93%

Role of Na_V1.7 in postganglionic sympathetic nerve function in human and guinea‐pig arteries

Kim,

Meeker,

et al. 2024

The Journal of Physiology

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NaV1.7 plays a crucial role in inducing and conducting action potentials in pain‐transducing sensory nociceptor fibres, suggesting that NaV1.7 blockers could be effective non‐opioid analgesics. While SCN9A is expressed in both sensory and autonomic neurons, its functional role in the autonomic system remains less established. Our single neuron rt‐PCR analysis revealed that 82% of sympathetic neurons isolated from guinea‐pig stellate ganglia expressed NaV1.7 mRNA, with NaV1.3 being the only other tetrodotoxin‐sensitive channel expressed in approximately 50% of neurons. We investigated the role of NaV1.7 in conducting action potentials in postganglionic sympathetic nerves and in the sympathetic adrenergic contractions of blood vessels using selective NaV1.7 inhibitors. Two highly selective NaV1.7 blockers, GNE8493 and PF 05089771, significantly inhibited postganglionic compound action potentials by approximately 70% (P < 0.01), with residual activity being blocked by the NaV1.3 inhibitor, ICA 121431. Electrical field stimulation (EFS) induced rapid contractions in guinea‐pig isolated aorta, pulmonary arteries, and human isolated pulmonary arteries via stimulation of intrinsic nerves, which were inhibited by prazosin or the NaV1 blocker tetrodotoxin. Our results demonstrated that blocking NaV1.7 with GNE8493, PF 05089771, or ST2262 abolished or strongly inhibited sympathetic adrenergic responses in guinea‐pigs and human vascular smooth muscle. These findings support the hypothesis that pharmacologically inhibiting NaV1.7 could potentially reduce sympathetic and parasympathetic function in specific vascular beds and airways. imageKey points 82% of sympathetic neurons isolated from the stellate ganglion predominantly express NaV1.7 mRNA. NaV1.7 blockers inhibit action potential conduction in postganglionic sympathetic nerves. NaV1.7 blockade substantially inhibits sympathetic nerve‐mediated adrenergic contractions in human and guinea‐pig blood vessels. Pharmacologically blocking NaV1.7 profoundly affects sympathetic and parasympathetic responses in addition to sensory fibres, prompting exploration into the broader physiological consequences of NaV1.7 mutations on autonomic nerve activity.

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“…48,77,78,80–89,91–94,99–101 Lilly and their collaborators reported the antitussive effects of compound 801, a sulphonamide-based Na V 1.7 inhibitor, on citric acid-evoked coughing in guinea pigs. 108,109 Recently, Merck reported a battery of four translational assays using rhesus monkeys: 1) microneurography for the action potential propagation in unmyelinated afferents, 2) threshold tracking for the excitability of myelinated afferents, 3) heat nociception test using clinical thermode device and 4) functional magnetic resonance imaging (fMRI) for olfactory function. Their sulphonamides exerted dose-dependent and significant effects in microneurography, heat nociception and fMRI assays.…”

Section: Pharmacological Effects Of Nav17 Inhibitors In In Vivo Anima...mentioning

confidence: 99%

Inhibition of Na_V1.7: the possibility of ideal analgesics

Kitano

Shinozuka

2022

RSC Med. Chem.

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Antitussive effects of NaV 1.7 blockade in Guinea pigs

Cited by 8 publications

References 46 publications

A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity

A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity

Role of Na_V1.7 in postganglionic sympathetic nerve function in human and guinea‐pig arteries

Inhibition of Na_V1.7: the possibility of ideal analgesics

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Antitussive effects of NaV 1.7 blockade in Guinea pigs

Cited by 8 publications

References 46 publications

A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity

A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity

Role of NaV1.7 in postganglionic sympathetic nerve function in human and guinea‐pig arteries

Inhibition of NaV1.7: the possibility of ideal analgesics

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Product

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Role of Na_V1.7 in postganglionic sympathetic nerve function in human and guinea‐pig arteries

Inhibition of Na_V1.7: the possibility of ideal analgesics