Genetic Influences on Pain Perception and Treatment
On a daily basis, pain practitioners encounter a curious clinical phenomenon. Patents with seemingly the same painful condition may report a wide difference in pain severity. Their response to equal treatment may also vary widely. This frustrating situation is now being at least partially explained by new genetic research. Presented here are some clinical pain problems and their relationship to genetic makeup that helps to explain the wide variations in pain perception and treatment response.
The completion of the human genome project in 2003 has provided a better understanding of why patients may experience pain syndromes. A genome is defined as all the deoxyribonucleic acid (DNA) in an organism, including its genes. DNA is defined as a molecule that carries all of our genetic information in all cell types except the red blood cell. DNA is like an instruction manual; it tells the body how to put something together. Genes located in the DNA carry information for making all the proteins required by each organism; genes are the words in the instruction manual. This information is encoded by four chemical nucleotides: adenosine, cytosine, guanine, and thymine (A, C, G, and T), which are the letters in the words of the instruction manual. The sequence of these letters determines which proteins (i.e., enzymes) are made. The proteins—the “building blocks” of an organism—determine, among other things, how the organism looks, metabolizes food, or fights infection, and sometimes even how it behaves. Knowledge about the effects of DNA variations among individuals can lead to revolutionary new ways to diagnose, treat and, hopefully someday, prevent the disorders that plague mankind.
Pain Is Genetically Influenced
Substantial evidence from preclinical models suggests that basal nociceptive sensitivity—neural processes of encoding and noxious stimuli—as well as antinociceptive responses to drugs show significant heritability. Evidence of genetic influences on pain sensitivity in humans has yet to be clinically applied. Polymorphisms—the normal differences in DNA sequences among individuals in a population—of receptors, transporters, metabolizing enzymes, and targets of pharmacotherapy are under investigation. To refer to the instruction manual analogy, polymorphisms are viewed as the different languages in which the instruction manual is written. It has the same information, but in a different form. Identifying a genetic predisposition to pain will allow pain to be treated with a genetic mindset and individualize treatment to each patient’s pain situation. It is estimated that about 10% of the general population experiences chronic pain at any given time.1 This paper explores the genetic influences on specific human musculoskeletal pain perception.
From a Darwinian perspective, nociceptive pain is impossible to eliminate nor is it desirable to do so. Nociception is essential for survival and, if a variation in a pain mechanism gene alters the function of a nociception-related molecule, the survival rate would be diminished. For instance, without pain mechanisms, people would not recognize the danger of leaving their hand on a hot stove. Mutations leading to decreased pain sensitivity occur in well under 1% of the population and lead to frequent injuries and inadvertent self-mutilation, which are incompatible with longevity or transmission to offspring.2 The limited number of individuals who have this mutation makes it difficult to produce a strong study, as that would require a large number of participants. While it is necessary to perceive pain from a survival standpoint, we must strive to manage pain pathways when they go awry and fire in the absence of noxious stimuli.
The Quantitative Trail Locus Concept
Men and women experience pain differently. Quantitative trait locus (QTL) refers to the inheritance of an observable trait—a phenotype—that varies in degree and is attributable to the interactions between two or more genes and their environment. When looking at a pillow, it is the pillowcase covering the pillow that is seen, not the pillow itself. However, you can deduce the size and shape of the pillow based on the pillow case you can see. It is the same with QTLs. Although not genes themselves, QTLs are stretches of DNA that are closely linked to the genes that underlie the trait in question. The identification of QTLs can help map regions of the genome that contain genes involved in specifying a trait. There have been two findings of gender-specific QTLs. The first concerns how the body processes painful stimuli. The second is a female-specific QTL for non-opioid stress-induced analgesia. This demonstrates the gender/genotype interactions of relevance to the process of pain perception. The gender-specific QTLs on autosomes—non-sex chromosomes—do not imply that each gender possesses or expresses different genes, but rather that the different genes are associated with trait variability in each gender. The existence of gender-specific QTLs does, however, imply that males and females possess at least partially independent physiological mechanisms underlying the traits in question.3
Disease-Specific Genetic Variants
In addition to gender specific QTL’s, there are also disease susceptibility variants that exhibit parental-origin-specific effects. For instance, a person’s risk of developing type II diabetes increases by 30 percent if genetic material is inherited form the father but decreases by 10 percent if inherited from the mother.4 Sequence variants that can provide risk and protection depending on parental origin may promote diversity and balanced selection. Even when associated with parental-origin-specific variants of established traits, it is underestimated. As this author speculates, this may be influenced by the fact the sequenced human genome is a compilation from different people—including male and female—or by the fact that it has missing sections. In an effort for anonymity in the sequenced genome, we may have blindfolded ourselves to useful information.
A single-nucleotide polymorphism (SNP) is a variation in the DNA sequence when a single nucleotide in the genome differs between members of a species or between paired chromosomes in an single individual. For example, two DNA fragment sequences from different individuals, AACA to AATA, contain a difference in a single nucleotide. In this case, we say that there are two alleles: C and T. A study on the AII8G SNP of the mu-opioid receptor gene (OPRME) was also linked to gender differences in the perception of pain. Genotyping of OPRMI showed that the rare AII8G allele had significantly higher indices of pressure-pain threshold that those with two alleles—homozygous—for the common allele. This allele occurred in 25 percent of females and 17 percent of men studied. The conclusion was that this genotype may be associated with pain perception in a sex-dependent manner and this rare allele is associated with higher indices of pressure-pain thresholds.1