Adult‐onset hypothyroidism causes mechanical hypersensitivity due to peripheral nerve hyperexcitability based on voltage‐gated potassium channel downregulation in male mice

Abstract

Thyroid hormones play an important role in the central and peripheral nervous system functions. Approximately 50% of adult‐onset hypothyroid patients have sensory symptoms including pain, possibly caused by peripheral neuropathy. However, the mechanism causing the pain has not been clarified. We generated an adult‐onset hypothyroid model animal by administering 50 ppm propylthiouracil (PTU) for 5 weeks to male mice. Female mice were not tested in this study. Mechanical hypersensitivity, determined by the von Frey hair test, was observed during the PTU exposure and recovered after the exposure termination. The sciatic nerve compound action potential was also analyzed. Under single‐pulse stimulation, no significant change in the threshold and conduction velocity was observed in the PTU‐administered group. On the other hand, under train‐pulse stimulation, the latency delay in the Aδ‐fiber component was less in the PTU‐administered group in Week 4 of PTU exposure, indicating relative hyperexcitability. Fluticasone, which is the anti‐inflammatory agent with an ability to activate the voltage‐gated potassium channel subfamily A (Kv1), restored the decrease in the latency change ratio by PTU exposure under the train‐pulse stimulation supporting our hypothesis that Kv1 may be involved in the conductivity change. Kv1.1 protein level decreased significantly in the sciatic nerve of the PTU‐administered group. These results indicate that adult‐onset hypothyroidism causes mechanical hypersensitivity owing to hyperexcitability of the peripheral nerve and that reduction of Kv1.1 level may be involved in such alteration.

Impaired autonomic function and somatosensory disturbance in patients with treated autoimmune thyroiditis

“…The pathomechanism remains unclear. Possible mechanisms include inflammation as well as down-regulation of potassium channels 60 due to hypothyroidism, oxidative stress and glial cell apoptosis via TSH signalling 61 and modulation of the TRPV1 and TRPM8 receptor properties by endogenous thyroid hormone metabolites [62][63][64][65] .…”

Network pharmacology and pharmacological evaluation of Wenzheng Jiedu Powder Modified Formula for neuropathic pain relief

“…According to pathway enrichment analysis of the core targets, these targets are mainly involved in the thyroid hormone, estrogen, longevity regulating, and PPAR signaling pathways, which are related to the NP development. The study of Suda et al (2022) found that thyroid hormones are vital for central and peripheral nervous system functions. About 50% of adults with adult-onset hypothyroidism experience sensory symptoms, including pain, potentially due to peripheral neuropathy (Suda et al 2022).…”

“…The study of Suda et al (2022) found that thyroid hormones are vital for central and peripheral nervous system functions. About 50% of adults with adult-onset hypothyroidism experience sensory symptoms, including pain, potentially due to peripheral neuropathy (Suda et al 2022). Moreover, gender differences in the manifestation of pain are well-documented (Bartley and Fillingin 2013), with a pivotal role attributed to estrogen (Qu et al 2015).…”