The processing of thermoreceptive information in the central nervous system of mammals begins in the dorsal horn of the spinal cord, where specialized neurons receive convergent input selectively from cold or warm thermoreceptors. Both warm- and cool-sensitive cells summate input from a large number of peripheral thermoreceptors over broad areas of skin. This summation is fundamental for overcoming ambiguous temperature responses received from individual thermoreceptors.

Cool-sensitive neurons in the spinal cord have ongoing discharge activity at normal skin temperature (34 °C [93 °F]). This activity is inhibited by warming but is stimulated by cooling, increasing in a linear fashion as temperature drops. At about 15 °C (59 °F) discharge activity becomes relatively constant and stays constant even as temperatures fall below this. In an inverse manner warm-sensitive spinal neurons have ongoing discharge that is inhibited by cooling. These neurons are stimulated by warming, increasing their activity linearly as temperature increases to about 45 °C (113 °F), at which point their activity plateaus. Thermoreceptive spinal neurons are specific. Thus, their activity closely reflects the activity of the peripheral thermoreceptors, and their response patterns parallel human temperature perceptions. In contrast, other spinal neurons show mechanical and weak thermal sensitivity, because they receive input from the thermally sensitive, slowly adapting mechanoreceptors in the skin.

Spinal thermoreceptive neurons send their activity to regions in the brainstem, where they affect the autonomic control of blood flow and respiration, or to the forebrain, where their activity leads to sensation. The cells that project to the forebrain send their axons up the spinal cord on the opposite side of the body in the so-called “lateral spinothalamic tract.” Humans or other animals experiencing certain types of pain may undergo a rare surgical procedure known as percutaneous cordotomy, which interrupts the lateral spinothalamic tract, thereby reducing pain. This interruption, as a rule, eliminates temperature sensation in mammals (along with pain, itch, and touch sensation, though a neuropathic pain condition may emerge later). In monkeys and humans this spinal thermoreceptive pathway extends upward along the spinal cord, eventually reaching a compact set of neurons that are part of a sensory processing structure known as the thalamus, which is located in the middle of the forebrain.

The neurons in the thalamus that receive input from the thermoreceptive-specific pathway also show selective thermoreceptive properties, and they are organized in a three-dimensional (topographic) map of the body. Microstimulation with fine electrodes in the thalamus can be performed during neurosurgical procedures for movement disorders. In these procedures patients are awake, and if the microelectrode is positioned inferior and posterior to the main somatosensory nucleus, microstimulation elicits immediate patient descriptions of discrete cooling, warming, or pain sensations localized to a particular part of the body. The thermoreceptive-specific neurons in the thalamus relay activity to a dedicated site in the cerebral cortex. Research has indicated that the specific receiving site is in the superior margin of the posterior insular cortex on the side of the brain contralateral to the body area represented. Functional imaging with positron emission tomography (PET) has confirmed that activation of this area of the cortex of the human brain is directly correlated with the sensation of skin temperature (either cool or warm). Damage to the cortex in humans may affect temperature sensation, though sensation can return.

It is important to recognize that the sensory region in the cortex of primates is part of a larger area that represents all aspects of the physiological condition of the body. This cortical area modulates the activity of regulatory regions in the brainstem and hypothalamus that maintain the health of the body, that is, regions involved in the process known as homeostasis. The organization of the thermosensory system in the brain indicates that the discriminative thermosensory capacity of humans has evolved as one aspect of the enormous encephalization that has produced a direct sense of the physiological condition of the body.