The Genetics of Pain: An Integrated Approach

Jun 13 • Biopharmaceutical, Featured • 1683 Views • Comments

Pain is a major symptom in many medical conditions, and can significantly interfere with a person’s quality of life and general functioning.[1]. It is often caused by intense or damaging stimuli, such as stubbing a toe, burning a finger, putting alcohol on a cut, and bumping the “funny bone.”

English: Illustration of the pain pathway in R...

Pain is an absolutely unpleasant one. Knowing the time of onset, location, intensity, pattern of occurrence (continuous, intermittent, etc.), exacerbating and relieving factors, and quality (burning, sharp, etc.) of the pain will help the examining physician to accurately diagnose the problem. For example, chest pain described as extreme heaviness may indicate myocardial infarction, while chest pain described as tearing may indicate aortic dissection.

Acute pain is usually managed with medications such as analgesics and anesthetics. Management of chronic pain, however, is much more difficult and may require an interdisciplinary approach for treating or easing the suffering and improving the quality of life. Psychological factors such as social support, hypnotic suggestion, excitement, or distraction can significantly modulate pain’s intensity or unpleasantness.

The International Association for the Study of Pain (IASP) states that “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.[2].

Following is the IASP’s classification of pain:

(1) region of the body involved (e.g., abdomen, lower limbs),

(2) system whose dysfunction may be causing the pain (e.g., nervous, gastrointestinal),

(3) duration and pattern of occurrence,

(4) intensity and time since onset, and

(5) etiology

This system has been criticized byClifford J. Woolf and others as inadequate for guiding research and treatment.

According to Woolf, there are three classes of pain :

Nociceptive painis caused by stimulation of peripheral nerve fibers and the stimulants could be Thermal, Mechanical and/ or Chemical. For example “heat or cold” (thermal), “crushing, tearing, etc.” (mechanical) and “iodine in a cut, chili powder in the eyes” (chemical).

Inflammatory pain: is associated with tissue damage and the infiltration of immune cells, and

Pathological pain: is a disease state caused by damage to the nervous system (neuropathic pain) or by its abnormal function (dysfunctional pain, like in fibromyalgia, irritable bowel syndrome, tension type headache, etc.).[3]

Pain will have a very detrimental effect on the quality of life. Experimental subjects challenged by acute pain and patients in chronic pain experience impairments in attention control, working memory, mental flexibility, problem solving, and information processing speed.[4]. Acute and chronic pain are also associated with increased depression, anxiety, fear, and anger.[5].

Patients who often have a background level of pain controlled by medications and whos pain periodically “breaks through” the medication is called breathrough pain and it is common in cancer patients . The characteristics of breakthrough cancer pain vary from person to person and according to the cause.

Harold Merskey said: “If I have matters right, the consequences of pain will include direct physical distress, unemployment, financial difficulties, marital disharmony, and difficulties in concentration and attention…”

Pain perception (point at which the stimulus begins to hurt) and tolerance thresholds (point at which the individual can’t tolerate the pain any more and when the subject acts to stop the pain) are not the same. The perception of pain is influenced by a multitude of variables including gender, age, mood, ethnicity and genetic factors [6],

Thus it is important to:

  • understand mechanisms of susceptibility to (chronic) pain,
  • Explore the genetics, emphasizing the conservation of pain-related genes, their functions and their advantages if any
  • Understand the role of gene polymorphisms in normal and pathological modulation of pain in models, humans, and as future drug targets
  • Explore the latest findings from human genome-wide investigation of genomic variability and gene expression on pain
  • Understand genetic and genomic techniques to study genetic contribution to (human) pain.
  • Study the progress of cutting-edge clinical trials and translate research findings to clinical practice
  • develop preventative approaches and novel treatment strategies

Advances in molecular, statistical and behavioral methodologies have suddenly allowed genetic investigations of complex biological phenomena, including pain. Genetic studies of pain are already showing their power to identify new molecular targets for drug development and create new animal models of pain pathology, says Jeffrey S. Mogil, PhD who is currently the E.P. Taylor Professor of Pain Studies and the Canada Research Chair in the Genetics of Pain and wrote a book on “The Genetics of Pain“.

Pain genetics can explain why we’re not all alike with respect to pain – why some people hurt more, and receive less benefit from existing analgesics. The knowledge gained holds the promise of allowing truly individualized pain therapy, says Mogil.

Algorithms for accessing and integrating available public data to examine disease-relevant mechanisms are of growing interest as publically available data sets grow at an ever-increasing rate. A meta-analysis of publicly available microarray data from rodents exposed to neuropathic or inflammatory pain was able to efficiently prioritize pain-related genes [7].

A similar approach using human gene expression data could be highly beneficial in generating data-driven hypotheses for pain genetics.

Most recent article, published on June 7, 2012, in open access journal  PLoS Computational Biology, on “Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases” presented a novel integrative approach that combines publicly available molecular data and automatically extracted knowledge regarding pain contained in the literature to assist the discovery of novel pain genes. This study was approved by the Institutional Review Boards of Stanford University and SRI International.

In this meta-analysis, they took advantage of the vast amount of existing disease-related clinical literature and gene expression microarray datastored in large international repositories and

  • Ranked thousands of diseases according to the Figure shown below.

  • Obtained gene expression profiles of 121 of these human diseases from public sources.
  • Selected ‘genes with expression variation significantly correlated with DSPI across diseases’ as candidate pain genes.
  • Genotyped selected candidate pain genes in an independent human cohort, and finally
  • Evaluated for significant association between variants and measures of pain sensitivity.

In this study, the genes were chosen based on their high correlation with the DSPI and plausible biology as assessed by the available literature and human expression profile across tissue using The Scripps Research Institute BioGPS database [8].

The selected genes were:

  • ABLIM3 (actin binding LIM protein family, member 3),
  • PDE2A (phosphodiesterase 2A, cGMP-stimulated),
  • CREB1 (cAMP responsive element binding protein 1),
  • NAALAD2 (N-acetylated alpha-linked acidic dipeptidase 2), and
  • NCALD (neurocalcin delta).

These genes were selected from the candidate list and were prospectively tested for variants that may be associated with differential pain sensitivity in an independent human cohort.

ABLIM3 was selected as the top candidate as it showed the highest correlation with the DSPI. ABLIM3 is a newly characterized protein-coding gene. ABLIM3 is expressed in various tissues, most prominently in muscle and neuronal tissue[9][10].

Polymorphisms in ABLIM3 (rs4512126) and NCALD (rs12548828, rs7826700, and rs1075791) showed significant association with the cold pressor pain threshold

The strongest signal was with rs4512126 (5q32, ABLIM3, P = 1.3×10−10)  for the sensitivity to cold pressor pain in males, but not in females – a sex-specific association.”

Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (P = 1.7×10−4, 1.8×10−4, and 2.2×10−4 respectively).

Authors said that, “This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates.”

Authors have demonstrated the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical datacurated from MEDLINE to facilitate the discovery of pain-relevant genes. This approach was validated through a targeted genetic association study in an independent human cohort, where variants of selected pain gene candidates were evaluated for associations with experimental pain sensitivity measures in humans.

Authors hope that “the outlined approach can complement existing research efforts by assisting the formulation of data-driven hypotheses, and may serve as a template to discover genetic components of other clinically important phenotypes.

Further Reading:

Pain Gene Database (PGD)[11]

MeSH: Medical Subject Heading is a comprehensive vocabulary thesaurus organized in a hierarchical structure allowing the indexing of publications with various levels of specificity.

The 20 diseases with the highest disease-pain ratio from the DSPI are listed out of a total of 2962 diseases are

.

 

Curated by: Dr. V. S. Karra, Ph.D.

 Posted in Bone Disease, Cardiovascular Pharmaceutical Genomics, Cell Biology and Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics,Computational Biology and Bioinformatics, Genome Biology, Genomic Medical Research, Genetics & Pharmaceutical, Innovations in Cancer Therapy, Pharmacotherapy Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Uncategorized | Tagged Chronic pain, Clifford J. Woolf, health, intensity pattern, medicine, myocardial infarction, Pain, Pain management, peripheral nerve fibers, Quality of life 

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