TRIGEMINAL NEURALGIA IN RATS WITH HYPOTHYROIDISM: A MORPHOLOGICAL STUDY

Thyroid hormones (THs) are important growth and development factors, mainly of the Central Nervous System (CNS). The lack of THs decreases the neuronal volume, the number of cells of the glia and may causing defects in myelination, which includes the spinal tract of the trigeminal nerve. Hypothyroidism (HT) is associated with chronic peripheral lesion in rats, depressing neuronal excitability with absence of sensory potentials. Previously, our lab research group verified that rats with HT have a higher nociceptive threshold when stimulated in the infra‐orbital region. The aim of this study was to evaluate the peripheral morphological changes in the trigeminal pathway in a HT model induced by propylthiouracil (PTU) drug in rats. 72 male Wistar rats (180–220 g), originating from the Central Animal Facility of the Federal University of Ceará ‐ Brazil, kept at 22 °C, by day/night cycle ‐ 12/12 h, with water and food ad libitum . The rats were divided into 6 groups: control (C), Trigeminal Neuralgia (TN), TN Sham, HT, HT+TN, HT+TN Sham. The HT was induced with 0.05% PTU for 21 days and confirmed by T4 dosing and histopathology. The weight gain was monitored every 3 days. NT was induced by infraorbital nerve (ION) constriction. The nociceptive threshold was measured using electronic Von Frey on days 0, 3, 7, 10, 14, 18 and 21 after TN induction. The animals were euthanized and the thyroid, ION, and trigeminal ganglion (TG) were collected. Immunofluorescence analysis was performed using the anti‐MBP and DAPI antibody in nerve and anti‐NeuN and anti‐ATF‐3 antibody in TG. Statistical analysis was performed by mean ± SEM of the measures recorded, by ANOVA analyze with Turkey pos‐hoc test, Student t test, both with significance level p<0.05. We found that the average dose of T4 was higher in groups that not receipt PTU while compared to groups treated with PTU (122.8 ng/mL ‐ 14.1 ng/ml, respectively, p<0.0001, Figure 1A). In histopathology analysis, we found a thyroid follicle retraction and absence of thyroglobulin colloid ( Figure 1D). In addition, an intense decrease in weight gain was observed ( Figure 1B), confirming the HT model. In the analysis of the nociceptive threshold at the 21st day (post‐induction) ( Figure 1C), it was verified that the HT and HT+TN Sham groups presented pain threshold higher than that observed in group C (p<0.0001). On the other hand the TN group showed a very reduced nociceptive threshold in relation to Control and other groups (p<0.0001). In contrast, in spite of neuralgia, the HT+TN group had a reduced nociceptive threshold when compared to the TN group (p<0.0001), but with a similar threshold that of group C (p=0.790). When we analyzed the anti‐MBP markers on ION, a significant increase in MPB expression was identified in the TN and HT+TN groups indicating a significant axonal lesion ( Figure 2A). In addition, we observed that anti‐ATF3 markers on TG shows a large expression of ATF3 in the cell bodies of neurons in the TN and HT+TN groups showing cellular response to the damage ( Figure 2B). Thus, we conclude that although the behavioral test suggests that HT can reduce the effects of neuropathy by increasing the nociceptive threshold, the expressions of MBP and ATF3 show us the opposite, HT actually potentiates the effects of peripheral neuropathy. To the best of our knowledge, this is the first report to demonstrate that the increase in the nociceptive threshold caused by HT is related to a failure of conduction due to the potentiation of the axonal lesions in the HT associated with Neuralgia. Support or Funding Information None.Graphical abstract of (A) Hormonal analyzes (T4), (B) Weight and (C) Nociceptive threshold. (D) Histopathological analysis of thyroid glands (Hematoxylin Eosin staining, 40×)Immunofluorescence analysis of (A) anti‐MBP in infraorbital nerve tissue and (B) anti‐ATF3 in trigeminal ganglion tissue.