title: Pain modality- and sex-specific effects of COMT genetic functional variants.
abstract: The enzyme catechol-O-methyltransferase (COMT) metabolizes catecholamine neurotransmitters involved in a number of physiological functions, including pain perception. Both human and mouse COMT genes possess functional polymorphisms contributing to interindividual variability in pain phenotypes such as sensitivity to noxious stimuli, severity of clinical pain, and response to pain treatment. In this study, we found that the effects of Comt functional variation in mice are modality specific. Spontaneous inflammatory nociception and thermal nociception behaviors were correlated the most with the presence of the B2 SINE transposon insertion residing in the 3'UTR mRNA region. Similarly, in humans, COMT functional haplotypes were associated with thermal pain perception and with capsaicin-induced pain. Furthermore, COMT genetic variations contributed to pain behaviors in mice and pain ratings in humans in a sex-specific manner. The ancestral Comt variant, without a B2 SINE insertion, was more strongly associated with sensitivity to capsaicin in female vs male mice. In humans, the haplotype coding for low COMT activity increased capsaicin-induced pain perception in women, but not men. These findings reemphasize the fundamental contribution of COMT to pain processes, and provide a fine-grained resolution of this contribution at the genetic level that can be used to guide future studies in the area of pain genetics.
authors.affiliation: Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA. belferi@upmc.edu
authors.forename: Inna
authors.initials: I
authors.lastname: Belfer
authors.forename: Samantha K
authors.initials: SK
authors.lastname: Segall
authors.forename: William R
authors.initials: WR
authors.lastname: Lariviere
authors.forename: Shad B
authors.initials: SB
authors.lastname: Smith
authors.forename: Feng
authors.initials: F
authors.lastname: Dai
authors.forename: Gary D
authors.initials: GD
authors.lastname: Slade
authors.forename: Naim U
authors.initials: NU
authors.lastname: Rashid
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mogil
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Campbell
authors.forename: Robert R
authors.initials: RR
authors.lastname: Edwards
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Eric
authors.initials: E
authors.lastname: Bair
authors.forename: William
authors.initials: W
authors.lastname: Maixner
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002211:Capsaicin / Q000633:toxicity; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D010146:Pain / Q000139:chemically induced / Q000235:genetics*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018689:Sensory System Agents / Q000633:toxicity; D012727:Sex Characteristics; D013045:Species Specificity; D055815:Young Adult
chemical_list: D018689:Sensory System Agents; D002394:Catechol O-Methyltransferase; D002211:Capsaicin