Our present understanding of the neuromolecular biology underlying pain perception should allow several aspects of pain treatment to be radically improved in the near future. For example, better analgesics could be created based on an improved understanding of how pain perception arises and how it travels within the nervous system. The genetic variations underlying pain perception can be genetically analyzed and applied directly to patient care.
Instead of an analgesic “hit and miss” approach, molecular analysis of the variants in an individual’s pain-associated genes would allow for a far more accurate assessment of the treatments needed to safe and effective pain treatment (i.e., “pain genotyping”). The technology to do this already exists and is commonly applied in other molecular pathologic tests.
Since the neuromolecular biology underlying pain perception appears to be highly conserved in all vertebrates, the study of pain perception-associated gene activities sheds light on animal pain perception. The present data strongly supports that animals perceive pain as well, or nearly as well as do humans. This data has important implications for how we treat animals.
It might be possible to alter the human genome to eliminate or reduce pain signals, to help individuals with chronic pain syndromes, or those who literally have a painful genetic inheritance, without the need of constant and sometimes dangerous pharmacologic interventions. Researchers at the University of Pittsburgh have demonstrated a gene therapy for neuropathic pain in an animal model as one example.
Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage1” Physical pain perception (nociception) is adaptive and protects complex organisms from tissue damage while inducing tissue protective and healing promoting behaviors.
Pain responses are found in all complex organisms, including fish, amphibians, reptiles, birds, and mammals. Although conscious pain perception cannot currently be measured in animals, adverse behavioral changes following painful events (reduced with analgesia), demonstrate that animals almost certainly perceive pain. Additionally, as pain perception is mediated by neocortical function (found in all vertebrates), and pain-inducing stimuli elicits very similar global vertebrate brain gene expression pattern changes, there is little reason based on behavioral, neuroanatomic, or molecular studies to doubt that most animals experience pain – for mammals, probably very similar to human pain perception.
Medically, untreated pain is a major problem in the US, with 50% of hospitalized patients being undertreated for pain, and 56% and 82% of individuals with cancer and HIV being similarly undertreated, respectively. See for example http://www.aapainmanage.org/literature/Articles/PainAnEpidemic.pdf.
However, over the past ten years, our understanding of the genetics underlying pain perception has vastly increased. Presently some three hundred-gene products have been identified which either modulate, or cause severe gains or losses in pain perception abilities. Based on identical human twin studies with comparison to data from mice, there are about twenty-four genes that carry common variations that significantly contribute to pain perception. The activities of these genes fall into four broad categories; 1) alterations in the activity and metabolism of exogenous or exogenous pain-modulating agents (such as enzymes that alter opiate metabolism), 2) enzymes that modulate activity other gene products involved in pain perception, 3) genes products (proteins) that regulate the movement of sodium or potassium across neural membranes, and 4) genes that regulate central nervous system development. The degree to which pain perception can by genetically altered is quite striking. For example, mice subjected to selective breeding and genetic attenuation/ablation of specific pain perception genes show a 1.2 to 54-fold variation in different pain sensitivity models and significantly differ in their responses to morphine-induced pain relief.
The significance of human genetic variations in pain perception is complex. For example, they can profoundly affect pharmacologic analgesia. Some individuals carry a change in the mu-opioid receptor gene, where a thymine is substituted for a cytosine at the gene sequence position 802. These individuals require very large doses of morphine for pain control. The genetic change almost completely blocks signaling from the mu-opioid receptor – a receptor that plays an important role in opioid pain analgesia. Another variation of this gene at position 118 results in decreased analgesic effects following opioid administration, but also protects from opioid toxicity, particularly respiratory depression. Other gene variations altering opioid drug metabolism can have profound effects. For example, the CYP2D6 gene product removes methyl (-CH3) groups from codeine, turning it into morphine. Some individuals carry variations of this gene that are unusually efficient at methyl group removal (demethylators). For these individuals codeine therapy is often ineffective and they can experience codeine toxicity from even a moderate dose. Additionally, there are tragic examples of breast-feeding “efficient demethylator” women on codeine who have poisoned their breast-feeding child with morphine, due to their usually fast ability to metabolize codeine to morphine.
Genetic variations in pain perception genes also alter daily pain perception. In one study, a variation in the SCN9A gene, termed “A” was shown to increase pain perception in individuals with osteoarthritis, pancreatitis, sciatica, phantom pain following amputation, and chronic back pain, vs. a more common “B” gene variation. Molecular analysis of the A and B SCN9A variations revealed that the A variation protein was more efficient at moving Sodium ions through its channel than the B variation. This difference would result in increased channel activity and heightened pain perception. In the same study 186 healthy women had their SCN9A genes analyzed and those with the A gene variation showed higher C-nerve fiber activity – a nerve fiber associated with pain perception. Interestingly, rare examples exist of complete SCN9A gene activity loss. These individuals have “Channelopathy-Associated Insensitivity to Pain” They show normal intelligence and are neurologically intact, but cannot perceive pain. These individuals are prone to sustaining severe and sometimes life-threatening injuries due to their inability to feel pain. (e.g. Ronald Niedermann the blonde giant from the Millenium Trilogy)
Other mutations of SCN9A gene cause “Primary Inherited Erythromelagia” a condition consisting of episodic skin redness, vasodilatation, and burning pain in the lower legs and feet following exercise or heat exposure. Interestingly, acid exposure is painful to all known species except the naked mole rat. These animals carry a SCN9A gene variation that specifically prevents pain perception with acid exposure. This is most likely an adaptation to the high carbon dioxide/low oxygen levels found in the tunnels where these animals live. Such an environment could cause acidosis (increased tissue acidity). The SCN9A gene variation would prevent these animals from experiencing acidosis-induced chronic pain, enhancing their ability to survive in an acidic environment. This provides a rare example of evolutionary pressures lessening pain perception to promote a species survival.
The functions of most pain perception associated genes are as yet incompletely understood and they often exert effects unrelated to pain. For example, variations of the SCN9A gene promote prostrate and breast cancer spread (metastasis), while the CYP2D6 gene variants play an import role in antidepressant and Tomoxifen (a breast cancer drug) metabolism. Additionally, many of these genes either add to, lessen, or oblate pain perception, changing the effects of other pain perception genes. These interactive effects are as yet poorly understood. Last, many of these gene variants alter one or a few aspects of pain, but not all, as in the naked mole rat SCN9A gene variation that allows most pain perception, but not that from acidosis. Mapping the “pain types” associated with specific gene types and variants has just begun. Additional funding and research is required to advance the state of the art and eliminate chronic and debilitating pain.
1International Association for the Study of Pain, 1979.
(Artist Credit: Many thanks to the amazing Naoto Hattori for use of Untitled 4 and Bad Day, please see http://naotohattori.com/home.html for more of his work.)
For more information on research into pain and pain management, the following links may be of interest.
Symposium on Genetics of Pain: http://www.paingenetics.org/
Journal of Pain Research: http://www.dovepress.com/journal-of-pain-research-journal
International Association for the Study of Pain (IASP) Grants:
Stanford Pain Management Center: http://paincenter.stanford.edu/research/
Arthritis & Chronic Pain Research Institute: http://www.pain-research.org/
American Pain Society: http://www.ampainsoc.org/
Genetic basis of pain variability: recent advances
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