Phenotype Partial analgesia Increased/decreased pain sensitivity Decreased pain sensitivity, decreased opioid analgesia [52,53] Increased/decreased pain sensitivity Example Reference(s) [35] [26,58,65,66] Increased pain sensitivity Decreased pain sensitivity Altered analgesic efficacy Altered morphine sensitivity Increased pain sensitivity [67] [39,68] [58] [67,69] [59] [61] [58] Loss of function SNPs? Partial analgesia, increased analgesic responsiveness doi:10.1371/journal.pgen.1000086.t001 lack of correlation. Negative correlation implies the presence of common pathways acting in opposing directions, or in a competitive manner. For example, a particular factor may sensitise mechanical but reduce thermal nociception, with high- and low-expressing strains resulting in the negative correlation observed. These nociceptive clusters may have a physiological basis. Sensitivity to analgesics, including gabapentin, morphine, and NSAIDS, is also affected by genetic factors in rodents [38]. For example, variations in the melanocortin-1 receptor gene have been shown to affect m-opioid analgesia in both mice and humans [39], and KCNJ9 (GIRK3) has been identified as a locus affecting analgesia from multiple drug classes [40]. In humans, the genetic contribution to variation in pain sensitivity has been investigated using twin studies, comparing correlation of pain thresholds between monozygotic (shared genetic and environment) and dizygotic (shared environment) twins. Two recent papers investigating responses to experimentally induced pain reported genetic contributions to sensitivity to the majority of pain modalities. Norbury et al. [41] performed quantitative sensory testing on almost 100 pairs of female twins, using a wide range of noxious stimuli and including models of Table 2. Heritable Pain Conditions. hyperalgesia and allodynia. Genetic components of 22%–55% were reported for the majority of painful stimuli, particularly heat pain thresholds, including burn, burn-evoked mechanical allody- nia, and iontophoresis of acid or ATP. Nielsen et al. [42] performed a similar study, investigating the genetic contribution to contact heat and cold pressor painful stimuli in a similar sample size. Sixty percent of the variance in cold pressor pain was predicted to be genetically mediated, compared with only 26% of the variance in heat pain. Interestingly, the factors influencing pain ratings were only loosely correlated between pain modalities, with genetic factors common to both modalities accounting for only 7% and 3% of the variance in cold pressor and heat pain, respectively. This is likely to be due to the nature of the cold stimulus used in this study, acting mainly through venous rather than cutaneous nociceptors [43] and therefore through a distinct neuronal pathway. Alternatively, the low correlation may reflect genetically encoded differences in primary transduction mecha- nisms. The differences in genetic contributions to various pain modalities in humans may reflect the distinct types of nociception described by Mogil et al. [24], probably representing peripheral or central mechanistic differences in the perception of different pain Table 1. SNPs Suggested To Affect Human Pain Sensitivity. Gene GCH1 COMT OPRM1 OPRD1 MC1R TRPA1 TRPV1 CYP2D6 ABCB1 FAAH Protein GTP cyclohydrolase Catechol-O-methyltransferase Opioid receptor m1 Opioid receptor d1 Melanocortin 1 receptor Transient receptor potential V1 Cytochrome P450 2D6 ATP-binding cassette, B1 Fatty acid amide hydrolase Transient receptor potential A1 Multiple SNPs Mutation Multiple SNPs Multiple SNPs Multiple SNPs Multiple SNPs SNP SNP Multiple SNPs Multiple SNPs Syndrome HSAN-1 HSAN-2 HSAN-3 (Familial dysautonomia) HSAN-4 (CIPA) Gene Affected Autosomal dominant mis-sense mutations in serine palmitoyltransferase long chain base subunit 1 (SPTLC1) Mis-sense mutations in the protein kinase PRKWNK1 Splicing deficit in IkbKAP protein Loss of functional NGF receptor TrkA Mutilated foot rat d subunit of the (Cct4 ) gene Erythermalgia Paroxysmal extreme pain (familial rectal pain) Insensitivity to pain Point mutations in sodium channel NaV1.7 – increased excitability Point mutations in NaV1.7 - loss of inactivation Mis-sense mutations in NaV1.7 doi:10.1371/journal.pgen.1000086.t002 PLoS Genetics | www.plosgenetics.org July 2008 | Volume 4 | Issue 7 | e1000086 Cell Loss Apoptotic cell loss of sensory and other neurons Phenotype Pain and heat loss Developing sensory cell loss Developing loss of all sensation Failure in sensory neuron development Loss of most small diameter sensory neurons Loss of nociceptors No cell loss No cell loss No cell loss 6 Pain-free phenotype Congenital insensitivity to pain Ulceration and loss of pain sensitivity Chronic inflammation Mechanically induced extreme pain [8] Complete insensitivity to acute pain [7] Reference [70] [71] [72] [1] [73] [9]