The genetics of pain: a new frontier?

7 Oct 2014  |  Print

The genetics of pain: a new frontier?

The human response to pain is remarkably variable between individuals – even when the provoking stimulus, injury or disease is identical. This variability is particularly marked with chronic neuropathic pain.

Why is this so?

In the past, it was often attributed to environment factors like psychosocial influences, upbringing and culture. However, there is increasing evidence that genetic factors also play a key role in responsiveness to nerve injury, particular with regard to chronic pain.

Animal models have played a major role in elucidating this phenomenon. For example, in a rat model of neuropathic pain following nerve injury, animals showed widely varying pain scores. By mating ‘pain-prone’ animals with each other, and doing likewise with ‘pain-protected’ animals, there was a clear separation into two distinct phenotypes within a few generations. This therefore demonstrated the potential heritability of pain predisposition.[1]

How gene variants affect pain

Genetic influences on pain act in different ways. Some may affect susceptibility to a disease that is painful, while others may affect susceptibility to pain itself.

However, pain is a sensory and emotional experience, whereas genes simply encode proteins. So how do we get from genetic (and therefore protein) variations to differences in sensory experience? It appears that both direct and indirect mechanisms are responsible.[2,3]

Direct mechanisms include disease-causing mutations that disturb pain pathways. A good example is a rare condition known as familial erythromelalgia, which is characterized by episodes of burning pain, erythema and swelling in the hands and feet. A single point mutation in a specific sodium channel (known as Nav1.7) in sensory neurons underlies this condition.[2] The point mutation radically alters the gating properties of the channel, leading to increased firing of the neuron and hence enhanced pain sensation.

Interestingly – and perhaps not surprisingly – other mutations in the same gene can have the reverse effect, reducing the responsiveness of sensory neurons. This leads to a heritable condition in which sufferers show reduced sensitivity to pain.

Indirect mechanisms by which genetic differences affect predisposition to pain may be more common. Genes can indirectly affect perception and even personality in a multitude of ways. For example, there are genes that appear to predispose individuals to traits as widely varying as generosity, risk taking, perfectionism and even smoking.[3]

How might this work with regard to pain susceptibility?

It is easy to imagine that a gene might encode for enhanced muscle development. Such an individual, with a toned, muscular body, might therefore have more self-confidence. As a result, they may undertake more risky activities, which might then leave them open to more painful experiences. Hence, a gene that directly impacts muscle development could also, indirectly, lead to greater risk-taking and enhanced pain susceptibility.

How are pain genes found?

A number of pain susceptibility genes have been identified in association studies.[4]

Animal models are an effective means of identifying potential pain genes of relevance in humans. For example, by taking two strains of mice with very different phenotypes in a neuropathic pain model – one strain demonstrating large amounts of pain behavior (‘pain prone’) and the other much less pain behavior (‘pain protected’) – it was possible to map the responsible gene to a specific region on mouse chromosome 15.[5] Using fine mapping strategies, it was then further located to a single locus.[6] This gene is known as CACNG2.

The protein encoded by CACNG2 is an important calcium channel subunit and has been implicated in the pathophysiology of epilepsy. Could it also play a role in the neuropathic pain response in humans? In a cohort of women who had undergone mastectomy, the presence of a particular haplotype of the CACNG2 gene was found to be a good predictor of chronic neuropathic pain, post-mastectomy.[6] Hence, CACNG2 could indeed be a valuable marker of pain predisposition.

What does this mean for future management?

Recent discoveries around pain susceptibility genes like CACNG2 may have great value in the future management of patients. For example, simple blood testing could be used to determine whether a woman who is about to undergo mastectomy has the susceptibility genotype. As a result, surgical procedures and pain management could be appropriately tailored in those women who are more likely to experience neuropathic pain.[7]

Understanding the genetic element of neuropathic pain may also have important implications for patients’ self-image. This could be particularly relevant in de-stigmatizing pain among patients suffering above-normal pain from a given injury.

Pain genetics therefore constitutes a new frontier in our understanding of chronic neuropathic pain. It has great potential in individualizing patient management and improving patients’ lives in the future.

References:

1. Devor M, Raber P. Heritability of symptoms in an experimental model of neuropathic pain. Pain 1990;42:51-67.
2. Catterall WA, et al. Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci 2008;28:11768-11777.
3. Ebstein RP, et al. Genetics of human social behavior. Neuron 2010;65:831-844.
4. McCaffrey P. Progress in Pain Genetics: A Meeting of Their Own. Report on the 10th IASP Research Symposium: The Genetics of Pain: Science, Medicine and Drug Development; 7-9 February 2012; Miami, Florida, USA. Available at: www.painresearchforum.org/news/14475-progress-pain-genetics-meeting-their-own. Accessed 4 September 2014.
5. Seltzer Z, et al. Mapping a gene for neuropathic pain-related behavior following peripheral neurectomy in the mouse. Pain 2001;93:101-106.
6. Nissenbaum J, et al. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Res 2010;20:1180-1190.
7. Nissenbaum J. From mouse to humans: discovery of the CACNG2 pain susceptibility gene. Clin Genet 2012;82:311-320.

RM-0657-V1-1014