Translating Pain – Genetics to Mice and Men and a Time Capsule from Montreal
By Adaora M. Chima, MBBS, MPH, from the IARS, AUA and SOCCA 2019 Annual Meetings*
Daniel Chartrand, MD, PhD, FRCPC, Luda Diatchenko, MD, PhD, and Jeffrey S. Mogil, PhD, from McGill University, provided a deep dive into translational pain research, the genetics of pain and the history of anesthesia in Montreal during the AUA Host Panel II.
A Time Capsule of Anesthesia in Montreal
Daniel Chartrand, MD, PhD, FRCPC, a connoisseur of anesthesia historical anesthesia facts, led the audience through the history of Canadian anesthesia founding fathers and their historical relationship with the International Anesthesia Research Society (IARS) and American Society for Anesthesiology (ASA). The history of the IARS, ASA, and Montreal dates back to the early 19th Century.
Following the famous demonstration of the effect of ether in the U.S., William Morton attempted to commercialize ether as Letheon. In January of 1847, a sales representative of his introduced the anesthetic agent to Drs. Horace Nelson and Webster. A month later, Webster had successfully removed a thigh mass in his patient’s home, under ether anesthesia. Nelson and Webster would go on to become Canadian Anesthesia pioneers.
Other historical Canadian figures include Dr. William Hingston, who was Mayor of Montreal in 1873. He successfully advocated for the use of ether instead of chloroform, which had a higher rate of perioperative adverse events. He also championed the case for physician-administered anesthesia care, a campaign that came to fruition shortly before his death.
In the 1920s, Drs. Bourne, Nagle and Geldert created the Canadian Society of Anesthesia, which eventually evolved into the Canadian Anesthesiologists Society in 1943. Francis Nagle was also the first anesthesiologist at McGill University.
A less known figure is Enid Johnson, a female physician who pioneered the use of curare for muscle relaxation with Harold Griffith at the Homeopathic Hospital of Montreal in 1942. Dr. Griffith went on to be president of CAS, IARS and a founder of WFSA. George Cousineau, one of the founders of CAS was responsible for the recognition of anesthesia as a specialty by the College of Physicians of Quebec.
What a historical treasure trove Montreal is for the field of anesthesia and perioperative medicine. Look out for the walking tour of the history of medicine in Montreal coming up on Saturday at the IARS 2019 Annual Meeting!
It’s in the Genes! The Genetics of Pain
Luda Diatchenko, MD, PhD, Canada Excellence Research Chair in Human Pain Genetics at McGill University, gave a presentation on the genetics of pain. She explained that although the molecular pathophysiology of pain remains unknown, the exploration of the human genome could help identify biologic markers and targets for pain treatment.
The challenge with developing a panacea for pain treatment lies partly in the existence of single nucleotide polymorphism (SNPs), which are variations in genetic building blocks in one person to the next. These variations result in polymorphism and mutations and contribute to the wide spectrum of pain frequency and perception experienced by different individuals. Variants can be rare with a high effect size and more common variants predominantly exhibiting a low effect size.
The neurotrophin receptor was the first gene associated with monogenic pain disorders to be identified. NAV1.7 is a sodium channel receptor which plays a role in nociception and has been gaining a lot of attention as a possible target for pain modulation.
Despite opinions to the contrary, strides have been made in translating genetic-based studies to clinical practice. Anti-NGF therapy has been effective in conditions like osteoarthritis that target neurotrophin receptors. Sodium channel receptors have also been targeted in pain pharmacotherapy. Research on EGFR and epiregulin interactions, COMT and OPRM genetic activity in pain processing mechanisms have been very promising.
Pain is a complex phenomenon that involves psychosocial factors, states of pain amplification, genetic influences and other synergistic factors, all of which are potential targets for pain management. Genetic and Phenotypic databases such as Human Pain Genes Database, UKBiobank are databank resources that will facilitate further exploration of the heterogeneity of chronic pain states, existing genetic variants and their varied responses to pharmacotherapy, and the potential application of risk stratification to pain management.
Ironic Adventures in Translating from Mice to Men
Jeffrey S. Mogil, PhD, of McGill University gave a rousing synopsis of the challenges in translational pain research. Translation from one species to another is a crucial juncture in biomedical research as many studies pertaining to human pharmacotherapy are primarily performed on a different species. As Dr. Mogil explained, one might intuitively expect that of the levels of the biopsychosocial model, the biological level would be the easiest to translate across species but this has proven to be very challenging.
One contributing factor is that pain research is predominantly performed using specific strains of male rats and mice. Microglia, which have been found to be part of the pain processing pathway in male mice, were discovered to be uninvolved in female mice. Also, studies have demonstrated differing responses to identical interventions among different strains of mice/rats. Due to differing biologic and personal health behaviors, there is more data on chronic pain disorders in female adult humans than any other demographic. Thus, chronic pain research studies performed on specific strains of male rats and mice will more likely be applied in clinical situations involving female patients. This problem with generalizability makes it difficult to translate such results for clinical application to a human population.
Another factor that has been identified is a difference in symptomatology that investigates animal models compared to human counterparts. Mechanical causes of pain are easier to demonstrate, replicate and measure in animals and thus are more frequently studied than spontaneous pain, which would be more challenging. Pain assessment tools for animals have also been problematic but progress has been made in developing tools such as grimace scales. Placebo vs. treatment trials have also seen a decline in the observed treatment advantage. This phenomenon has been more severe in the U.S.
A surprising finding on the social level of translational research is that lab mice have a social life that can be tracked. A study to assess whether mice avoid or approach pain showed gender related differences in behavior that were similar to human behavior in a similar situation. In the human species, females gravitated towards other females who exhibited signs of pain or an ailment. This was similarly observed in female mice. Males (men and mice) did not show a significant change in behavior that could be attributed to an observation of pain/sickness in a neighbor. In human males, this behavior changed in the presence of females.
These observations indicate that it might be easier to translate the results of animal-based research on a social level, than on a biologic level. That’s quite some food for thought.
*Coverage from the AUA Host Program Panel II at the AUA 2019 Annual Meeting