Experimental sepsis induces sustained inflammation and acetylcholinesterase activity impairment in the hypothalamus.

Sepsis is one of the leading causes of mortality in intensive care units besides causing profound alterations in the brain. One of the structures notably affected during sepsis is the hypothalamus, resulting in important physiopathological consequences. Recently, we provided evidence that the presence of neuroinflammation, oxidative stress, and apoptosis in the hypothalamus of septic rats, is accompanied by impairment of arginine vasopressin (AVP) secretion. We had also demonstrated that sepsis survivor animals present attenuated AVP secretion after osmotic challenge, suggesting a persistent inflammation in the hypothalamus. However, the long-term course of inflammation in the hypothalamus remains unclear. Thus, we induced sepsis by cecal ligation and puncture (CLP) in Wistar rats and, five days after sepsis induction, the hypothalamus of each animal was collected for analysis. Nonmanipulated animals (naive) were used as controls. We found that CLP-induced morphological alterations in microglial cells are accompanied by an increase in Iba-1 immunoreactivity. Moreover, we observed enhanced expression of NF-κB and CREB transcription factors, which are well known to modulate the immune response. Additionally, we found that phosphorylation of GSK3α/ß (a kinase upstream to the CREB signaling pathway) was increased, as well as COX-2, iNOS, and IL-6 that are canonic inflammatory proteins. Thus, our results indicated the presence of sustained activation of resident glial cells that may result in neuroinflammation and cholinergic neurotransmission disruptions in the hypothalamus.

Associating high intensity and modulated frequency of TENS delays analgesic tolerance in rats.

BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is a non-invasive analgesic resource extensively used in painful conditions. However, preclinical studies suggest that the prolonged use of TENS results in the development of tolerance to its analgesic effect. The present study investigated the analgesic effect and development of tolerance to TENS with four different stimulation protocols. METHODS: Male Wistar rats induced with joint inflammation were divided into four groups: sensory intensity, low motor intensity, high motor intensity and sham groups. TENS was applied daily for 20 min with alternating frequency between 4 and 100 Hz until tolerance development was evidenced. Mechanical hyperalgesia was measured before and after each TENS daily application. RESULTS: After TENS, tolerance was evidenced There was a significant reduction in the mechanical withdrawal threshold in all groups 24 h after induction of inflammation (p < 0.01). We observed a loss of analgesic efficacy of TENS around the 12th, 19th and 19th days in the groups treated with sensory intensity, low motor intensity and high motor intensity, respectively (p < 0.02) when analysed using paired measurements and compared with the control. CONCLUSIONS: The association between frequency variation and intensity at motor level promotes a delay in the development of analgesic tolerance to TENS, optimizing and extending its therapeutic effectiveness.

Experimental hypothyroidism during pregnancy affects nociception and locomotor performance of offspring in rats.

BACKGROUND: Thyroid hormones (THs) play a crucial role in the development of several organic systems. An adequate support of maternal THs may be required to ensure a normal nociceptive function of offspring into adulthood. We investigated the impact of experimental gestational hypothyroidism (EGH) on nociceptive threshold and motor performance in the offspring at different post-natal days (PND) in both male and female rats. METHODS: EGH was induced by the administration of 0.02% methimazole (MMI) in the drinking water from the ninth day of gestation until birth. The offspring from MMI-treated dams (OMTDs) or from water-treated dams (OWTDs) were assessed for thermal and mechanical nociception using the tail-flick test and von Frey filaments, respectively. Both rota-rod and grip strength were used to assess motor function. RESULTS: OMTD had reduced thermal (p<0.05) but not mechanical threshold at all studied ages (60 and 120 PND). Sixty-day-old OMTD presented reduced latency to the tail-flick test (p=0.01). Grip strength in 120-day-old OMTD was reduced (p<0.01). However, only male OMTD presented a lower locomotor performance on the rota-rod test when analysed on the 60th PND (p<0.01). CONCLUSIONS: EGH promotes hypersensitivity to noxious thermal but not mechanical stimulus. Moreover, motor force is similarly reduced in male and female OMTDs, whereas motor performance is reduced only in mature male OMTD, suggesting the presence of a protective factor in females.