Mice, like humans, show robust individual differences in their sensitivity to pain, pain inhibition, and susceptibility to chronic pain development after injury. Like all biological traits, some proportion of this variability is due to inherited genetic factors ("nature"), some proportion is due to environmental factors ("nurture"), and some proportion is due to the interaction of the two. The identification of the genes responsible for variability in pain traits is accomplished by quantitative trait locus (QTL) mapping followed by some combination of candidate gene testing and/or positional cloning. It's important to note that these "pain variability genes" represent a subset of all "pain genes," defined simply as genes coding for proteins of relevance to pain. The latter type of pain gene can be identified via conventional techniques, transgenic knockout experiments, and microarray gene expression profiling. A compilation of pain genes as defined by transgenic knockout experiments is provided in the Resources (Pain Genes Db) section of this website.
Using these techniques, the Pain Genetics Lab and collaborators have provided published evidence for the following genomic regions (and genes) associated with variability in pain.
Trait
Genomic Location
Sex Specificity?
Likely Gene
Hot Plate Test
Chr. 4, ≈70 cM
Male>Female
Oprd1 (delta-opioid receptor)
Formalin Test
Chr. 9, ≈60 cM
No
Atp1b3 (beta-3 subunit of the sodium-potassium pump)
Chr. 10, ≈70 cM
Male>Female
Avpr1a (vasopressin receptor 1A)
Paw-Withdrawal Test
Chr. 7, ≈55 cM
Female>Male
Calca (CGRP)
Spared Nerve Injury
Chr. 5, 123 Mb
No
P2rx7 (purinergic P2X7 receptor)
Morphine Analgesia
Chr. 1, ≈10 cM
Female Only
???
Chr. 9, ≈20 cM
Female Only
???
Chr. 9, ≈40 cM
No
Htr1b (5-HT receptor,1B)
Chr. 10, ≈10 cM
Male>Female
Oprm (mu-opioid receptor)
U50,488 (kappa-opioid) Analgesia
Chr. 8, ≈65 cM
Female Only
Mc1r (melanocortin-1 receptor)
The Pain Genetics Lab continues to work towards the identification of genomic regions associated with variability in pain-related traits, and in the identification of the responsible genes within these regions. Current projects are focused on genes relevant to mechanical allodynia after nerve injury and chronic inflammation. In addition to our QTL mapping efforts, much can be learned about pain by examining genetic correlations among pain-related traits. We have tested a common set of 12 inbred mouse strains (all genetically identical "clones" of each other) for many, many types of pain, analgesia, and related traits (including tolerance, dependence, itch). Traits in which the same strains are sensitive and resistant are traits in which variability is mediated by common genes, and thus common physiology. We have used genetic correlation analysis to define primary or fundamental types of pain, to infer the existence of "master" analgesia genes, and to demonstrate that the potency of analgesics in mice is dependent on the type of pain being inhibited.
