Cool receptors may provide relief for chronic pain
A study published in Current Biology shows that a receptor activated by cool temperatures and by compounds such as menthol has an analgesic effect in mice with sciatic nerve injuries. The findings could be useful in developing treatments for chronic and neuropathic pain, the latter of which occurs in the absence of external stimuli and is extremely difficult to treat.
Since ancient times it has been known that cooling has an analgesic effect. Menthol has been used as an ingredient in Chinese herbal medicines for hundreds of years, and clinical trials show that cooling can alleviate chronic back pain, postoperative pain and toothache. The mechanisms of cooling-induced analgesia are, however, unknown.
In the last decade, understanding of the mechanisms by which sensory neurons respond to temperature has advanced a great deal. Probably the best understood of these mechanisms is the one involving the heat-activated VR1 receptor; this receptor is also activated by capsaicin, a compound found in chilli peppers.
The receptor examined in this study, called transient receptor potential melastatin 8 (TRPM8), is an ion channel expressed in a subset of primary sensory neurons in the dorsal root and trigeminal ganglia of mice. The receptor is activated by temperatures of about 18 degrees Celcius and by menthol and icilin, a compound used as an ingredient in toothpaste and nasal sprays.
The work was carried out on mice in which the sciatic nerve had been constricted with ligatures. This serves as an animal model of neuropathic pain. The sensitivity to pain was measured by the tendency of the mice to withdraw their paws from a hot plate. In summary, the study shows that:
- TRPM8 expression up-regulated in the animal model of neuropathic pain;
- very low doses of icilin, injected directly into the spinal cord, markedly reduced the animals’ sensitivity to pain, and when mice were bathed for 5 minutes in an icilin solution, the analgesic effects lasted for up to 5 hours;
- knockdown of TRPM8 expression using antisense oligonucleotides abolished the analgesic effects of receptor activation;
- activation of the TRPM8 receptor caused hypersensitivity to pain;
- administration of metabotrobic glutamate receptor antagonists ablished the analgesic effects of TRPM8 atcivation
- very low doses of icilin, injected directly into the spinal cord, markedly reduced the animals’ sensitivity to pain, and when mice were bathed for 5 minutes in an icilin solution, the analgesic effects lasted for up to 5 hours;
The authors propose a mechanism whereby TRPM8 activation results in the release of glutamate, which then binds to inhibitory metabotropic glutamate receptors to block transmission of pain signals to the brain. This could occur either by autoinhibition, in whereby the glutamate acts on the cells which released it, or by the postsynaptic actions of glutamate on second order sensory neurons in the dorsal horn of the spinal cord.
The findings suggest that TRPM8 agonists or mGlu antagonists may be used to provide treatment for patients with chronic or neuropathic pain.
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