Intergenerational and lifelong chronic pain starting in early life

2nd year PhD students Jennaya Christensen (left)
and Sabrina Salberg (right)

Chronic pain is a costly public health issue that is highly prevalent and causes a great burden to people who are affected, their families, their workplaces and the health system. 

New research from the Monash Trauma Group at the Department of Neuroscience, Central Clinical School, Monash University shows that there is a difference both in gender and type of adverse childhood experience in the expression of specific biomarkers linked to chronic pain. 

Additionally, early life stress such as maternal separation, and a high-fat, high-sugar diet lead to higher pain sensitivity, increased anxiety-like behaviour and changes in the neurobiology (structural and functional level) of the brain.

Chronic pain often occurs during childhood, with 1 in 5 children or adolescents having reported it and it being more prevalent in females than males. 

Evidence has shown that chronic pain experienced in childhood and adolescence increases the risk of chronic pain and poor health outcomes including mental health disorders in adulthood. In addition, children and adolescents of parents who have chronic pain, have an increased risk of developing chronic pain.

Adverse childhood experiences, e.g. emotional or physical neglect, emotional, sexual, or physical abuse, and household dysfunction including a violent home environment and parental separation or divorce, have been linked with poor health conditions such as chronic pain in adolescents and adults. 

The intergenerational relationship between trauma and adverse childhood experiences in parents and chronic pain experienced in children is not well understood, in particular the neurobiological mechanisms which contribute to the relationship. An important genetic factor which may be influencing the transmission of chronic pain is known as epigenetics, which is persistent change in the expression of genes that do not affect the primary DNA sequence but alter the cellular activity and functional outcomes. Gene expression can be studied through biomarkers in blood and saliva. 

Associate Professor Richelle Mychasiuk

For the first time, in collaboration with researchers in the Departments of Psychology and Pediatrics at the University of Calgary, the Alberta Children’s Hospital Research Institute, and Hotchkiss Brain Institute in Canada the researchers have examined the relationship and mechanisms between adverse childhood experiences, gene expression (through specific biomarkers), chronic pain and negatively associated symptoms similar to PTSD in group of children and parents (1). 

The study, performed by PhD student Jennaya Christensen, supervised by Associate Professor Richelle Mychasiuk, used saliva samples to look at specific biomarkers with an established link to chronic pain or adverse childhood experiences. The biomarkers include catechol-O-methyltransferase (COMT), dopamine receptor D2 (DRD2), glucocorticoid receptor (GR) and serotonin transporter (SERT) with all parental adverse childhood experiences, with a focus on maltreatment and household dysfunction. 

This analysis revealed that there were gender specific differences in the expression of all of the biomarkers investigated. Further analysis resulted in distinct, significant gender differences with overall parental adverse experiences - and specifically maltreatment - being negatively correlated with child gene expression of dopamine receptor D2 in female children. In addition, overall parental adverse childhood experiences - and specifically household dysfunction - were altered for gene expression of COMT in the parents of male children. Hence, the risk of poor outcomes in female and male offspring through parental adverse childhood experiences may be transmitted through different biological pathways.

These may be used as objective biomarkers for identifying youth at risk for developing chronic pain and further, as targets for early intervention / prevention of chronic pain. 

“We have established that using saliva samples rather than blood is a viable and less invasive method.”

Associate Professor Richelle Mychasiuk said this is important as there are challenges in collecting blood samples in children and adolescents. For instance, the process of needle pricks can induce pain and anxiety which would affect the study findings, so this is a great way to solve that problem. And most importantly, limiting any unnecessary further pain and anxiety in this population is a critical advancement for our field. 

Jennaya hopes that this finding persuades researchers to adopt this non-invasive method of saliva collection for epigenetic analysis, which in turn could increase participant willingness to contribute to studies and eliminate the confounds associated with needle pricks.

First author PhD student Sabrina Salberg, in a related preclinical study looked at the how early life trauma-related factors, e.g. high-fat, high-sugar diet and maternal separation, affected pain outcomes in adolescence, and what the underlying mechanisms are that contribute to these outcomes (2). 

The group found that compared with controls, the high-fat, high-sugar diet altered the thermal and mechanical pain response, and maternal separation increased anxiety in adolescent rats following behavioural testing. Further, half of the animals underwent a mildly painful stimulus and were tested again after a recovery period to find out if the early life factors (e.g. high-fat, high-sugar diet and maternal separation) contributed to the development of chronic pain by modifying the underlying mechanisms that result in a pain response. The altered pain response and increased anxiety continued, providing key evidence for adverse childhood experiences resulting in chronic pain. 

To gain a more in depth understanding of neurobiological function and the underlying mechanisms, advanced magnetic resonance imaging was carried out in vivo using the ARA preclinical imaging facility. Changes in the brain volume and diffusivity were found in areas of the brain involved in reward processing and emotional regulation (e.g. amygdala, corpus callosum, thalamus and nucleus accumbens) following a high-fat, high-sugar diet and maternal separation. Sabrina commented that,

“The most exciting finding was seeing how quickly the changes in the brain could be observed following the mildly painful stimulus as a result of the early adverse experiences.” 

The group now hopes to investigate the gender differences they found by increasing the sample size and separating groups out further into distinct categories. 

These findings provide an insight into the factors that drive changes in the maturation of the brain and its abnormal response, e.g. exacerbated pain sensitivity and increased neurobiological function, revealing targets for early intervention or prevention in adolescents.

Funding was provided by the Canadian Institutes of Health Research and National Health and Medical Research Council (NHMRC)

References

• Christensen J, Beveridge JK, Wang M, Orr SL, Noel M, Mychasiuk R. A Pilot Study Investigating the Role of Gender in the Intergenerational Relationships between Gene Expression, Chronic Pain, and Adverse Childhood Experiences in a Clinical Sample of Youth with Chronic Pain. Epigenomes. 2021; 5(2):9. https://doi.org/10.3390/epigenomes5020009 
• Sabrina Salberg, Glenn R Yamakawa, Yannick Griep, Jesse Bain, Jaimie K Beveridge, Mujun Sun, Stuart J McDonald, Sandy R Shultz, Rhys D Brady, David K Wright, Melanie Noel, Richelle Mychasiuk, Pain in the Developing Brain: Early Life Factors Alter Nociception and Neurobiological Function in Adolescent Rats, Cerebral Cortex Communications, Volume 2, Issue 2, 2021, tgab014, https://doi.org/10.1093/texcom/tgab014