Table 1.

Genes involved with pain mechanisms

Gene name	Polymorphism	Pathway(s)	Reference(s)
Human κ opioid receptor gene (OPRK1)	In humans, the 36G > T single nucleotide polymorphism (SNP) on KOR gene	The κ opioid receptor (KOR) system seems to play a role in stress responsivity, opiate withdrawal and responses to psycho stimulants, inhibiting mesolimbic dopamine. KOR gene polymorphisms have been reported to contribute to predisposition to voluntary alcohol-drinking behavior in experimental animals	Gerra G, Leonardi C, Cortese E, D’Amore A, Lucchini A, Strepparola G, et al. Human kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction. Am J Med Genet B Neuropsychiatr Genet 2007;144(6):771–5
Mu opioid receptor	A118G SNP of the mu opioid receptor gene (OPRM1)	Mu opioid receptors are critical for heroin dependence, and A118G SNP of the mu opioid receptor gene (OPRM1) has been linked with heroin abuse. In our population of European Caucasians (n = 118), approximately 90% of 118G allelic carriers were heroin users	Drakenberg K, Nikoshkov A, Horváth MC, Fagergren P, Gharibyan A, Saarelainen K, et al. Mu opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers. Proc Natl Acad Sci USA 2006;16;103(20):7883–8
D(2) dopamine receptor gene (DRD2)	A haplotype block of 25.8 kb was defined by 8 SNPs extending from SNP3 (TaqIB) at the 5′ end to SNP10 site (TaqIA) located 10 kb distal to the 3′ end of the gene	Within this block, specific haplotype cluster A (carrying TaqIB1 allele) was associated with a high risk of heroin dependence in Chinese patients (P = 1.425 × 10(−22); odds ratio, 52.80; 95% confidence interval, 7.290–382.5 for 8-SNP analysis). A putative recombination ‘hot spot’ was found near SNP6 (intron 6 ins/del G), creating 2 new daughter haplotypes that were associated with a lower risk of heroin dependence in Germans (P = 1.94 × 10(−11) for 8-SNP analysis). Other studies show the relationship of carrying TAq1A1 vs A2 alleles in the treatment outcomes for heroin abuse. The results indicate that DRD2 variants are predictors of heroin use and subsequent methadone treatment outcome, and suggest a pharmacogenetic approach to the treatment of opioid dependence. Others found association between nasal inhalation of opiates and DRD2 promoter - 141 DeltaC polymorphism. Significantly stronger cue-elicited heroin craving was found in individuals carrying D2 dopamine receptor gene (DRD2) TaqI RFLP A1 allele than the non-carriers (P < 0.001)	Xu K, Lichtermann D, Lipsky RH, Franke P, Liu X, Hu Y, et al. Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in 2 distinct populations. Arch Gen Psychiatry 2004;61(6):597–606 Lawford BR, Young RM, Noble EP, Sargent J, Rowell J, Shadforth S, et al. The D(2) dopamine receptor A(1) allele and opioid dependence: association with heroin use and response to methadone treatment. Am J Med Genet 2000;96(5):592–8 Li Y, Shao C, Zhang D, Zhao M, Lin L, Yan P, et al. The effect of dopamine D2, D5 receptor and transporter (SLC6A3) polymorphisms on the cue-elicited heroin craving in Chinese. Am J Med Genet B Neuropsychiatr Genet 2006;141(3):269–73
ANKK1 gene	With a non-synonymous G to A transition, rs2734849 produces an amino acid change (arginine to histidine) in C-terminal ankyrin repeat domain of ANKK1	Since DRD2 expression is regulated by transcription factor NF-κB, we suspect that rs2734849 may indirectly affect dopamine D (2) receptor density. The rs273849 ANNK1 variant alters the expression level of NF-kappaB-regulated genes	Huang W, Payne TJ, Ma JZ, Beuten J, Dupont RT, Inohara N, et al. Significant association of ANKK1 and detection of a functional polymorphism with nicotine dependence in an African–American sample. Neuropsychopharmacology; 2008
Catechol-O-methyltransferase (COMT) gene	Val(108/158)met polymorphism of the catechol-O-methyltransferase (COMT) gene	Genotyping 38 Israeli heroin addicts and both parents using a robust family based haplotype relative risk (HRR) strategy. There is an excess of the val COMT allele (likelihood ratio = 4.48, P = 0.03) and a trend for an excess of the val/val COMT genotype (likelihood ratio = 4.97, P = 0.08, 2 df) in the heroin addicts compared to the HRR control group	Horowitz R, Kotler M, Shufman E, Aharoni S, Kremer I, Cohen H, et al. Confirmation of an excess of the high enzyme activity COMT val allele in heroin addicts in a family based haplotype relative risk study. Am J Med Genet 2000;96(5):599–603 Cao L, Li T, Xu K, Liu X. Association study of heroin dependence and -287 A/G polymorphism of catechol-O-methyltransferase gene]. In: Zhonghua Yi, Xue Yi, Chuan Xue, Za Zhi, editors. 2002;19(6):499–501
Proenkephalin gene (PENK)	> or =81 bp allele	Among the subjects with opioid dependence, 66% carried the > or =81 bp allele compared with 40% of subjects with other types of substance abuse (χ2 = 11.31, p < 0.004) and 49% of controls (χ2 = 6.0, p < 0.015). These results are consistent with a role of the PENK gene in opioid dependence. In another study, Heroin abuse was significantly associated with PENK polymorphic 3’ UTR dinucleotide (CA) repeats; 79% of subjects homozygous for the 79-bp allele were heroin abusers. Such individuals tended to express higher PENK mRNA than the 81-bp homozygotes, but PENK levels within the nucleus accumbens (NAc) shell were most strongly correlated to catecholamine-O-methyltransferase (COMT) genotype. Altogether, the data suggest that dysfunction of the opioid reward system is significantly linked to opiate abuse vulnerability and that heroin use alters the apparent influence of heritable dopamine tone on mesolimbic PENK and tyrosine hydroxylase function	Comings DE, Blake H, Dietz G, Gade-Andavolu R, Legro RS, Saucier G, et al. The proenkephalin gene (PENK) and opioid dependence. Neuroreport. 1999;10(5):1133–5 Nikoshkov A, Drakenberg K, Wang X, Horvath MC, Keller E, Hurd YL. Opioid neuropeptide genotypes in relation to heroin abuse: dopamine tone contributes to reversed mesolimbic proenkephalin expression. Proc Natl Acad Sci USA 2008;105(2):786–91
Serotonin transporter (hSERT)	Homozygosity at hSERT (especially 10/10) was associated with early opiate addiction, while genotype 12/10 proved to be protective	Reward system pathway	Galeeva AR, Gareeva AE, Iur’ev EB, Khusnutdinova EK. VNTR polymorphisms of the serotonin transporter and dopamine transporter genes in male opiate addicts. Mol Biol (Mosk). 2002;36(4):593–8 Bonnet-Brilhault F, Laurent C, Thibaut F, Campion D, Chavand O, Samolyk D, et al. Serotonin transporter gene polymorphism and schizophrenia: an association study. Biol Psychiatry 1997;42(7):634–6
Dopamine transporter (DAT1)	In the case of DAT1, genotype 9/9 was associated with early opiate addiction. The combination of hSERT genotype 10/10 with DAT1 genotype 10/10 was shown to be a risk factor of opiate abuse under 16 years of age	Reward system pathway	Galeeva AR, Gareeva AE, Iur’ev EB, Khusnutdinova EK. VNTR polymorphisms of the serotonin transporter and dopamine transporter genes in male opiate addicts. Mol Biol (Mosk). 2002;36(4):593–8
Cannabinoid CB1 (brain) receptor gene (CNR1)	A microsatellite polymorphism (AAT)n at the cannabinoid CB1 (brain) receptor gene (CNR1) consists of 9 alleles. The number of i.v. drugs used was significantly greater for those carrying the > or ≥ or = 5 genotype than for other genotypes (P = 0.005)	Cannabinoid receptors in the modulation of dopamine and cannabinoid reward pathways	Comings DE, Muhleman D, Gade R, Johnson P, Verde R, Saucier G, MacMurray J. Cannabinoid receptor gene (CNR1): association with i.v. drug use. Mol Psychiatry. 2000;5(2):128–30

We suggest that the seven genes (shown in Table 2) constitute a sampling of the proposed genes that should be tested prior to treatment of any painful condition because of the potential involvement in pain mechanisms, tissue healing and inflammation.