Genetics of pain, opioids, and opioid responsiveness
Introduction
The ability to sense pain (nociception) is variable in human populations as well as in animals; its heritability, genetic correlations, and linkage point to the importance of its genetic determinants [1]. Pain perception is a defense mechanism that alerts us to injury-producing events. The severity of pain is controlled by several genetic variants affecting the expression or function of nociceptive sensory system components. Migraine is among the first of painful diseases to be associated with a genetic component, and several of its variants have been identified [2], [3]. Pain is a common symptom of cancer and its treatment, and several genetic polymorphisms have been discovered to be associated with both cancer risk and cancer-induced pain [4]. Other pain syndromes are also under genetic control. Our understanding of the neurobiology of pain pathways has grown in the last decade, and several membrane receptors and channels that respond to pain-provoking stimuli have been found and characterized. This review will focus on the genetics of sensitivity to pain and opioid responses as well as its importance in the development of better pain therapies.
Section snippets
Rare hereditary syndromes of complete insensitivity to pain
The complete inability to sense pain is a very rare phenotype. Several hereditary syndromes that involve complete or almost complete insensitivity to pain have been discovered and are listed in the Online Mendelian Inheritance in Man database. They include channelopathy-associated insensitivity to pain syndrome, of which the most likely candidate gene is the α-subunit of the voltage-gated sodium channel Na(v)1.7, encoded by the gene SCN9A at locus 2q24.3. The gene is preferentially expressed in
The genetics of variable pain sensitivity in the general population
Abnormal responses to tissue injury are common in 1 of 6 adults suffering from a chronic pain condition [7]. Several genetic variants have been shown to modulate the generation, transmission, and processing of nociceptive information or the local availability of active analgesics and their pharmacodynamic effects. Each of them, however, has only a modest impact on the pain phenotype. Variable pain sensitivity in the general population has been associated with common variants of the μ-opioid
Pharmacogenomics of pain therapy
Genetic polymorphisms have been shown to contribute in part to interindividual variability in pain therapy. Opioids and other analgesic drugs are widely used to control moderate to severe pain. However, interindividual sensitivity and their severe adverse effects, such as dependence, tolerance, and respiratory depression, often hamper effective pain management. The MOP receptor is a preferred target of morphine, playing a crucial role in mediating the major clinical outcomes of morphine,
Studies in animal models
Most current knowledge on the genetic regulation of pain has been derived from monogenetic addition and subtraction models developed mainly in mice. The genetic control of pain has also been demonstrated in polygenic mouse models by quantitative sensory trait approaches [13]; and it has been noted that nociceptive responses behave as a continuous trait in 11 different inbred mouse strains, underlying its polygenic character. A behavioral quantitative trait locus-mapping strategy has recently
Personalized medicine in pain management
Knowledge of the genetic factors that affect opioid efficacy, metabolism, and adverse effects has the potential for personalizing both acute and chronic pain management, and for designing more useful opiate pain medications with lower adverse event profiles. For instance, it has long been recognized that genetic factors (specifically CYP2D6 whose absence makes codeine almost completely inefficient) predict individual responses to codeine administration [19], [20] or postoperative morphine
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Publication of this article was supported by the Collège International de Recherche Servier (CIRS).
STATEMENT OF CONFLICT OF INTEREST: The authors have nothing to disclose.