Cold thermosensation

Below is the introduction to my third and final piece of coursework, an essay entitled Multiple roles for Transient Receptor Potential Melastatin 8 (TRPM8) in cold thermosensation. This time, I discuss three recent studies which have contributed significantly to the understanding of the mechanisms by which nerve endings in the skin detect cold stimuli. I'll post the rest of the essay over the next few days, in 3 or 4 parts. The papers I discuss will be listed as references after the discussion section.

Summary: Here I discuss three recent studies which have contributed significantly to the understanding of cold thermosensation. McKemy et al (2002) cloned and characterized TRPM8; this was the first cold receptor to be identified. Dhaka et al (2007) generated TRPM8 knockout mice, and analysed the mutant phenotype to show that TRPM8 senses and transduces innocuous cool and noxious cold stimuli, and mediates cool-induced analgesia. Takashima et al (2007) investigated the distribution in the periphery of TRPM8-expressing sensory neuron nerve terminals; their findings provide an anatomical basis for the multiple roles of TRPM8 in cold thermosensation.

Primary sensory neurons of the trigeminal and dorsal root ganglia (TG and DRG, respectively) relay tactile, noxious and hot and cold stimuli from the periphery to the central nervous. These neurons have a single process which bifurcates close to the cell body. One branch projects into the superficial layers of the spinal cord, where it forms synapses with second order sensory neurons; the other branch projects into the periphery, where it innervates the skin.

Distinct subpopulations of TG and DRG are responsive specific types of stimulus. Some respond to innocuous stimuli such as light touch and small changes in skin temperature; others respond to noxious stimuli such as intense pressure, hot and/or cold temperatures (below ~28 degrees Celsius or above ~43 degrees Celsius) and irritant chemicals released from damaged cells. Some DRG cells respond to only one type of stimulus, while others are polymodal.

TG and DRG cells are also characterised anatomically by the size of the cell body and the diameter of the fibre, and functionally by action potential conduction velocity and sensory modality. A-beta fibres are classified as proprioceptors; they have large cell bodies, are thickly myelinated, and have a high conduction velocity. C-fibres have small cell bodies, and thin, unmyelinated fibres which conduct action potentials slowly; and A-delta fibres have cell bodies of an intermediate size. Most C-fibres, and some A-delta fibres, are polymodal nociceptors, which respond to multiple stimuli.

It has long been known that TG and DRG contain cells which respond to innocuous and noxious hot and cold temperatures. Until recently, however, nothing was known about the molecular mechanisms of thermoreception. But in the past decade, much progress has been made, largely because of the identification of the Transient Receptor Potential (TRP) family of ion channels. To date, six temperature-sensitive TRP channels have been identified. These channels have been named "thermoTRPs"; four of them are sensitive to heat, and two respond to cold (Dhaka et al, 2006).

In parts 2, 3 and 4, I discuss three studies which contributed significantly to the understanding of cold thermosensation. McKemy et al (2002) identified, and characterized TRPM8, the first cold receptor. Dhaka et al (2007) generated TRPM8 knockout mice, and showed that TRPM8 is required for sensing innocuous cool and that it mediates cooling-induced analgesia. They also show that the channel is involved in sensing noxious cold temperatures. Takashima et al (2007) used a genetic axon labeling method to visualize TRPM8-positive nerve endings, and showed that the primary sensory neurons which express TRPM8 are anatomically and neurochemically heterogeneous. Their findings also raise the possibility that cold fibres have a labeled line organization.