What Does the Cold Sensitivity Gene Have to Do With Migraines? (TRPM8)

The TRPM8 gene encodes the major sensory receptor of cold in our bodies. It is activated either by cold temperatures or by menthol (the active compound in peppermint), which is why mint makes our mouths feel cold [R].

TRPM8 becomes less sensitive in the presence of acidic pH and more sensitive in the presence of menthol [R, R].

This cold receptor plays a complex role in pain perception. In “hot” or burning pain, the heat receptor TRPV1 is activated and TRPM8 (which would produce a cooling sensation) is blocked. However, TRPM8 can also be sensitized to produce “cold” pain [R, R].

Adaptation to Climate

While a lot of genes show variation between different populations of people, TRPM8 is especially dramatic. A variant that increases TRPM8 expression is much more common in Northern Europeans than in Africans: 88% in Finland compared with 5% in Nigeria [R]!

TRPM8 makes us more sensitive to cold sensations. One might think that reduced cold sensitivity would be an advantage for people living in cold climates, so it may seem strange that northern populations have increased TRPM8 expression. However, increased sensitivity to cold may cause increased production of body heat, among other adaptations [R].

Unfortunate Side Effects

People with a higher amount of TRPM8 might have an advantage in colder climates, but they’re also more susceptible to certain types of pain disorders. Most notably, the high-expression variant rs10166942-T is associated with IBS and migraines [R].

TRPM8 is activated by both cold temperatures and menthol, the active compound in peppermint. People in colder climates tend to have higher expression of TRPM8.

TRPM8 has been linked to migraines, but researchers haven’t completely nailed down how the connection might work. One possibility, emerging from a rodent study, is that the TRPM8 receptor can interact with a type of serotonin receptor called 5-HT1B and suppress hypersensitivity to pain [R].

Serotonin receptors, in turn, are heavily implicated in migraines. Triptans, a common class of drugs prescribed to treat a migraine in progress, work by binding to the serotonin receptors 5-HT1B and 5-HT1D. Once activated, these receptors constrict the blood vessels in the brain, counteracting the painful widening of these vessels during a migraine attack [R, R].

Thus, TRPM8 might work like a kind of natural triptan, encouraging blood vessels to constrict and preventing hypersensitivity to pain. However, some evidence seems to suggest that increased TRPM8 expression is linked to increased susceptibility to migraines, so the direction of effect isn’t clear [R, R, R].

TRPM8 interacts with a type of serotonin receptor, 5-HT1B, which constricts the blood vessels and prevents hypersensitivity to pain. Scientists suspect that this mechanism could be behind TRPM8’s link to migraines.

Three variants of TRPM8 have been associated with migraines, and one has been linked to how well a migraine patient responds to triptan medications.

Migraine Incidence

The three variants of TRPM8 associated with the presence or absence of migraine are rs10166942, rs7577262, and rs17862920 [R, R, R].

The best-studied of these is rs10166942, at which each copy of the minor ‘T’ allele is associated with a greater incidence of chronic migraines. People with one copy of the ‘T’ allele tend to have migraines more often than those without a ‘T’ allele, and those with two copies (the ‘TT’ genotype) tend to have migraines more often than those with one [R, R, R, R, R].

At rs7577262, the minor ‘A’ allele may be somewhat protective against migraine. Two studies have found that the ‘A’ allele is less common in people who experience migraines than in people who don’t [R, R].

Finally, the minor ‘T’ allele of rs17862920 may also be somewhat protective against migraine [R].

Response to Migraine Medication

At least one study has found a link between a TRPM8 variant and how well a migraine patient responds to triptans. At rs6724624, the ‘G’ allele was associated with an inconsistent triptan response [R].

The researchers cautioned that the link between rs6724624-G and triptan response might not be statistically significant. They also noted, however, that it was worth another look, given how TRPM8 seems to be involved in migraine more broadly [R].

The rs6724624 and rs10166942 variants appear to be inherited together. You can use the table below to see which rs6724624 alleles you are likely to carry based on the one you have atrs10166942.

Variants of the TRPM8 gene have been associated with the incidence of migraine and with how well a migraine patient responds to triptans.

SNP Summary and Table

TRPM8 rs10166942

• ‘C’ = Not associated with migraines
• ‘T’ = Associated with increased incidence of migraines
• About 29% of all people worldwide carry the ‘TT’ genotype.
• The ‘TT’ genotype is much more common in people of European (69%) and American (51%) descent and almost nonexistent in people of African descent (1.5%).

TRPM8 rs7577262

• ‘G’ = Not associated with migraines 
• ‘A’ = Possibly protective against migraines
• About 40% of all people worldwide carry at least one copy of the ‘A’ allele.
• The ‘A’ allele is significantly less common in people of European (17%) and American (16%) descent and more common in people of East Asian descent (64%).

TRPM8 rs17862920

• ‘C’ = Not associated with migraines
• ‘T’ = Possibly protective against migraines
• About 26% of all people worldwide carry at least one copy of the ‘T’ allele.
• The ‘T’ allele is significantly more common in people of East Asian (49%) and South Asian (41%) descent.

TRPM8 rs6724624

• ‘G’ = Less consistent response to triptans
• ‘C’ = More consistently successful response to triptans
• About 29% of all people worldwide carry the ‘CC’ genotype.
• The ‘CC’ genotype is much more common in people of European (69%) and American (51%) descent and almost nonexistent in people of African descent (1.5%).