Role of afferent pathways of heat and cold in body temperature regulation.

The detection of surface and internal temperatures is achieved by axons terminating at lamina I of the spinal dorsal horn, otherwise approached only by nociceptive afferents. Recent advances in thermal physiology research have disclosed that temperature-sensitive ion channels belonging to the "transient receptor potential" family exist in the peripheral sensory neurons and in the brain. Thermosensory, nociceptive and polymodal afferents project to different thalamic nuclei, and specific pathways to the insular cortex evoke the conscious experience of thermal sensation. The posterior insular region represents discriminative thermal sensation, while the largest correlation with subjective ratings of temperature is located in the orbitofrontal and anterior insular cortex. The insular cortex forms an integrative part of the limbic system and is closely tied with the hypothalamus, the amygdala, the anterior cingulate cortex and the orbitofrontal cortex and emerges as the main coordinator of behavioral, autonomic and endocrine responses to both non-noxious and noxious thermal stimuli. The firing rate of warm and cold receptors is not altered by pyrogens. A strong correlation between the onset of fever and production of superoxide by macrophages following the injection of pyrogens implicates reactive oxygen species as elicitors of fever, a hypothesis strengthened by the observation that oxygen radical scavengers or thiol reductants act as antipyretics. Oxidative stress appears to be sensed by the brain and a likely structure for its detection may be the redox-sensitive site of the N-methyl-D-aspartate (NMDA) receptor for glutamate, in that oxidation of this site causes fever while its reduction lowers body temperature, effects which are abrogated by specific NMDA receptor blockers.