Pain vulnerability and DNA methyltransferase 3a involved in the affective dimension of chronic pain

Abstract

Chronic pain with comorbid emotional disorders is a prevalent neurological disease in patients under various pathological conditions, yet patients show considerable difference in their vulnerability to developing chronic pain. Understanding the neurobiological basis underlying this pain vulnerability is essential to develop targeted therapies of higher efficiency in pain treatment of precision medicine. However, this pain vulnerability has not been addressed in preclinical pain research in animals to date. In this study, we investigated individual variance in both sensory and affective/emotional dimensions of pain behaviors in response to chronic neuropathic pain condition in a mouse model of chronic pain. We found that mice displayed considerably diverse sensitivities in the chronic pain-induced anxiety- and depression-like behaviors of affective pain. Importantly, the mouse group that was more vulnerable to developing anxiety was also more vulnerable to developing depressive behavior under the chronic pain condition. In contrast, there was relatively much less variance in individual responses in the sensory dimension of pain sensitization. Molecular analysis revealed that those mice vulnerable to developing the emotional disorders showed a significant reduction in the protein level of DNA methyltransferase 3a in the emotion-processing central nucleus of the amygdala. In addition, social stress also revealed significant individual variance in anxiety behavior in mice. These findings suggest that individual pain vulnerability may be inherent mostly in the emotional/affective component of chronic pain and remain consistent in different aspects of negative emotion, in which adaptive changes in the function of DNA methyltransferase 3a for DNA methylation in central amygdala may play an important role. This may open a new avenue of basic research into the neurobiological mechanisms underlying pain vulnerability.

Walking the Tightrope: A Proposed Model of Chronic Pain and Stress

“…This suggests that the underlying mechanism for pain exacerbation induced by inhibition of the G protein-coupled receptor 40/free fatty acid receptor 1 may be associated with naloxone-induced exacerbation of postoperative pain (Nakamoto et al, 2017). Using a chronic pain mouse model, Wang et al (2017) investigated individual variance in two dimensions of pain behaviors: sensory and emotional. Results showed that mice displayed heterogeneous sensitivities in the chronic pain-induced anxiety-and depression-like behaviors of affective pain.…”

“…Results showed that mice displayed heterogeneous sensitivities in the chronic pain-induced anxiety-and depression-like behaviors of affective pain. Additionally, their molecular analyses revealed that the mice with higher vulnerabilities to developing emotional disorders, such as depression and anxiety, also revealed to have lower levels of protein in the amygdala, and more specifically, in the emotion-processing central nucleus (Wang et al, 2017). Their findings suggest that individual vulnerabilities to pain may be ingrained in the emotional aspect of chronic pain and remain consistent in aspects of negative emotions, in which adaptive changes in the role of the changed protein levels in central amygdala may have significant and longterm consequences.…”

SIRT1 Decreases Emotional Pain Vulnerability with Associated CaMKIIα Deacetylation in Central Amygdala

“…However, in preclinical research using animal models of chronic pain, the affective/emotional component of chronic pain has been much less studied, possibly due to the extended time (ϳ4 weeks) required to induce behaviors of negative emotion (vs minutes to induce sensory pain) in animal models and, importantly, to the large individual variance that often results in nonsignificant changes in comparisons of group averages. Recently, a growing number of preclinical studies have demonstrated that chronic sensory pain can induce anxietyand depression-like behaviors in rodents (Narita et al, 2006; Caspani et al, 2014; Barthas et al, 2015;Wang et al, 2015Wang et al, , 2017Gambeta et al, 2018). Nevertheless, in contrast to well docu-mented clinical reports of individual vulnerability to the development of chronic pain in patients (Denk et al, 2014), pain vulnerability remains severely understudied in pain research on animal models.…”

Modulation of the Negative Affective Dimension of Pain: Focus on Selected Neuropeptidergic System Contributions

“…Epigenetic studies produced significant results in this field. In this regard, mice subjected to partial nerve ligation (PNL) exhibit a significant and long-lasting sensitization of sensory pain compared to sham-operated animals, accompanied by minimal individual variance [119]. On the other hand, the assessment of the affective behavior associated with neuropathic conditions disclosed interesting results.…”

“…However, results showed that PNL animals were clearly divided into two different groups, vulnerable and resilient to stress. Surprisingly, statistical analysis highlighted no differences between the sham group and PNL stress-resistant mice [119]. Subsequent molecular experiments showed that chronic neuropathy promotes a significant down-regulation of the DNMT3a enzyme isoform in the central nucleus of AM, mainly in vulnerable animals.…”