Selection of preferred thermal environment and cold-avoidance responses in rats rely on signals transduced by the dorsal portion of the lateral funiculus of the spinal cord.

Thermoregulatory behaviors are powerful effectors for core body temperature (Tc) regulation. We evaluated the involvement of afferent fibers ascending through the dorsal portion of the lateral funiculus (DLF) of the spinal cord in "spontaneous" thermal preference and thermoregulatory behaviors induced by thermal and pharmacological stimuli in a thermogradient apparatus. In adult Wistar rats, the DLF was surgically severed at the first cervical vertebra bilaterally. The functional effectiveness of funiculotomy was verified by the increased latency of tail-flick responses to noxious cold (-18°C) and heat (50°C). In the thermogradient apparatus, funiculotomized rats showed a higher variability of their preferred ambient temperature (Tpr) and, consequently, increased Tc fluctuations, as compared to sham-operated rats. The cold-avoidance (warmth-seeking) response to moderate cold (whole-body exposure to ~17°C) or epidermal menthol (an agonist of the cold-sensitive TRPM8 channel) was attenuated in funiculotomized rats, as compared to sham-operated rats, and so was the Tc (hyperthermic) response to menthol. In contrast, the warmth-avoidance (cold-seeking) and Tc responses of funiculotomized rats to mild heat (exposure to ~28°C) or intravenous RN-1747 (an agonist of the warmth-sensitive TRPV4; 100 µg/kg) were unaffected. We conclude that DLF-mediated signals contribute to driving spontaneous thermal preference, and that attenuation of these signals is associated with decreased precision of Tc regulation. We further conclude that thermally and pharmacologically induced changes in thermal preference rely on neural, presumably afferent, signals that travel in the spinal cord within the DLF. Signals conveyed by the DLF are important for cold-avoidance behaviors but make little contribution to heat-avoidance responses.

Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis.

Antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel alter body temperature (Tb) in laboratory animals and humans: most cause hyperthermia; some produce hypothermia; and yet others have no effect. TRPV1 can be activated by capsaicin (CAP), protons (low pH), and heat. First-generation (polymodal) TRPV1 antagonists potently block all three TRPV1 activation modes. Second-generation (mode-selective) TRPV1 antagonists potently block channel activation by CAP, but exert different effects (e.g., potentiation, no effect, or low-potency inhibition) in the proton mode, heat mode, or both. Based on our earlier studies in rats, only one mode of TRPV1 activation - by protons - is involved in thermoregulatory responses to TRPV1 antagonists. In rats, compounds that potently block, potentiate, or have no effect on proton activation cause hyperthermia, hypothermia, or no effect on Tb, respectively. A Tb response occurs when a TRPV1 antagonist blocks (in case of hyperthermia) or potentiates (hypothermia) the tonic TRPV1 activation by protons somewhere in the trunk, perhaps in muscles, and - via the acido-antithermogenic and acido-antivasoconstrictor reflexes - modulates thermogenesis and skin vasoconstriction. In this work, we used a mathematical model to analyze Tb data from human clinical trials of TRPV1 antagonists. The analysis suggests that, in humans, the hyperthermic effect depends on the antagonist's potency to block TRPV1 activation not only by protons, but also by heat, while the CAP activation mode is uninvolved. Whereas in rats TRPV1 drives thermoeffectors by mediating pH signals from the trunk, but not Tb signals, our analysis suggests that TRPV1 mediates both pH and thermal signals driving thermoregulation in humans. Hence, in humans (but not in rats), TRPV1 is likely to serve as a thermosensor of the thermoregulation system. We also conducted a meta-analysis of Tb data from human trials and found that polymodal TRPV1 antagonists (ABT-102, AZD1386, and V116517) increase Tb, whereas the mode-selective blocker NEO6860 does not. Several strategies of harnessing the thermoregulatory effects of TRPV1 antagonists in humans are discussed.

Intracerebral Injection of Streptozotocin to Model Alzheimer Disease in Rats.

Animal models have promoted meaningful contribution to science including Alzheimer's disease (AD) research. Several animal models for AD have been used, most of them related to genetic mutations observed in familial AD. However, sporadic form of AD, also named late-onset is the most frequent form of the disease, which is multifactorial, being influenced by genetic, environmental and lifestyle factors. Here, we describe a protocol of an AD-like pathology of the sporadic form using Wistar rats by a single bilateral intracerebroventricular (icv) injection of streptozotocin (STZ, 2 mg/kg). Icv injection of STZ induces brain resistance to insulin and other pathological alterations related to those observed in AD, such as cognitive impairment and accumulation of phosphorylated tau protein and ß-amyloid in the brain. Thus, icv injection of STZ is a useful tool to investigate the pathological mechanisms and the metabolic alterations involved in AD and to propose new therapeutic approaches and neuroprotective drugs.