Epigenetic regulation of chronic pain

Here are three recent scientific full-text PMC articles about how chronic pain induces epigenetic changes which in turn may then also affect the pain in a feedback loop.

Epigenetic regulation of chronic pain  – PMC4422180 – 2016 Apr


Chronic pain arising from peripheral inflammation and tissue or nerve injury is a common clinical symptom.

Inflammation-, tissue injury-, and/or nerve injury-induced changes in gene expression in sensory neurons of the dorsal root ganglion (DRG), spinal cord dorsal horn, and pain-associated brain regions are thought to participate in chronic pain genesis; however, how these changes occur is still elusive.  

Epigenetic modifications including DNA methylation and covalent histone modifications control gene expression.

This review summarizes the current knowledge and progress in epigenetic research in chronic pain and discusses the potential role of epigenetic modifications as therapeutic antinociceptive targets in this disorder.


Peripheral inflammation and nerve injury produce transcriptional and translational changes in the expression of

  • receptors,
  • enzymes,
  • ion channels,
  • neurotransmitters,
  • neuromodulators, and
  • structural proteins in primary sensory neurons of dorsal root ganglion (DRG), spinal cord, and other pain-related regions in the brain.

These changes contribute to the induction and maintenance of chronic pain; however, how these changes are regulated by peripheral noxious stimuli is still not fully understood.

Recent studies have suggested that the mechanism for gene regulation involves epigenetic modifications.

Environmental toxins, medications, diet, and psychological stress alter epigenetic processes such as

  • DNA methylation,
  • covalent histone modification (e.g., acetylation and methylation), and
  • non-coding RNA expression.

Accumulating evidence demonstrates that these processes play an important role in synaptic plasticity during memory formation as epigenetic changes correlate with hippocampal activity

This article focuses on the evidence for the changes in DNA methylation and histone modification, mostly in DRG and spinal cord, under chronic pain conditions.

We explore how these changes are induced by peripheral noxious stimuli and how these epigenetic processes regulate pain-related genes.

We finally deduce potential mechanisms of how the changes in DNA methylation and histone modification contribute to the development and maintenance of chronic pain.

The article goes on to describe the technical details.

Future perspectives

Given that chronic pain remains a challenging condition to manage and that the contribution of epigenetic mechanisms underlying this disorder is becoming increasingly recognized, it is conceivable that the significance of histone modification and DNA methylation in chronic pain will become even more apparent in the coming years.

Epigenetic regulation of persistent pain – 2016 Jan


Persistent or chronic pain is tightly associated with various environmental changes and linked to abnormal gene expression within cells processing nociceptive signaling.

Epigenetic regulation governs gene expression in response to environmental cues.

Recent animal model and clinical studies indicate that epigenetic regulation plays an important role in the development/maintenance of persistent pain and, possibly the transition of acute pain to chronic pain, thus shedding light in a direction for development of new therapeutics for persistent pain.


Persistent or chronic pain is a complicated clinic condition that impacts the lives of approximately a quarter of the population.

This clinic condition can be developed from acute pain resulting from tissue damage or be associated with numerous human diseases.

Similar to varied individual pain sensitivity, there is a large difference in vulnerability of individuals to develop persistent pain.

Although the mechanisms underlying this variation remain largely unknown, efforts have been spent to look for genetic mechanisms and gene expression.

It has been well established from clinical and laboratory studies that under persistent pain conditions cells processing pain signaling, i.e., nociceptors in the peripheral nervous system and neurons/glia in the central nervous system, become sensitized in response to various stimuli.

This increased sensitivity is accompanied by functional and structural changes (plasticity).

Multiple molecular mechanisms are likely responsible for these changes. Various chemicals/factors and relevant receptor/signal transduction pathways are proposed to become active during persistent pain

Gene-specific and genome-wide association studies (GWAS) further demonstrate that many genes undergo expression changes at mRNA and protein levels in tissues/cells of pain circuitry during the development/maintenance of persistent pain

Cases of single nucleotide polymorphisms (SNPs) have been found to be risk factors in the development of persistent pain in humans

Epigenetic regulation has been found to participate in many physiological and pathological processes, such as neuronal plasticity and cancer, in which various environmental factors are involved and sometimes, however, no cell division occurs

In most of these cases, genetic mechanisms fail to explain the changes. Environmental factors such as stress, tissues damage and disease conditions largely impact the vulnerability of individuals to develop persistent pain clearly via DNA sequence-independent mechanism(s). This concept is supported by several lines of evidence

The article goes into considerable technical detail explaining this evidence.

Epigenetic Mechanisms of Chronic Pain – 2015 Jun


Neuropathic and inflammatory pain promote a large number of persisting adaptations at the cellular and molecular level, allowing tissue or nerve damage, even if only transient, to elicit changes in cells that contribute to the development of chronic pain and associated symptoms

There is evidence that injury-induced changes in chromatin structure drive stable changes in gene expression and neural function, which may cause several symptoms, including allodynia, hyperalgesia, anxiety, and depression.

Recent findings on epigenetic changes in the spinal cord and brain during chronic pain may guide fundamental advances in new treatments.

In this review, we provide a brief overview of epigenetic regulation in the nervous system and then discuss the still-limited literature that directly implicates epigenetic modifications in chronic pain syndromes.

Notably, chronic and intense pain can have effects at the level of gene expression in spinal and supraspinal areas located far from the initial lesion and may include brain areas that are not directly associated with the processing of sensory information.

A growing number of studies directly implicate alterations in gene expression with the generation of certain chronic pain conditions, such as neuropathic or rheumatoid arthritis pain.

However, until recently, the mechanisms by which acute tissue injury and pain induce changes in gene expression for a prolonged period of time have remained poorly understood.

Epigenetic mechanisms provide a plausible process through which stable changes in CNS activity may manifest in response to peripheral injuries.

Epigenetic mechanisms drive long-lasting cellular and behavioral changes

Epigenetic mechanisms enhance or suppress gene expression without alterations of the primary DNA sequence.

Epigenetic mechanisms have been shown to be involved in synaptic plasticity, learning, and memory as well as in several neuropsychiatric disorders including depression and drug addiction.

These mechanisms include DNA methylation, several types of histone modifications (e.g., acetylation, methylation, phosphorylation, and ADP-ribosylation), and expression of microRNAs (miRNAs)

Epigenetic mechanisms can be dynamic and responsive to changes in experience, thus representing a complex interplay between an organism and its environment.

The article continues with extensive descriptions of these mechanisms.


3 thoughts on “Epigenetic regulation of chronic pain

  1. Laura P. Schulman, MD, MA

    This is really important stuff! And as I discovered during a most frustrating meeting with a highly placed faculty member at the Cleveland Clinic Spine Center, not everyone is happy that there is hard science backing up the theory of epigenetic pain modulation. I merely hinted at it, and he jumped up from his desk, screaming and jabbing his gigantic finger in my face…good thing I wasn’t there about my chronic pain, but merely wanted to know what my future is likely to look like with pan-spinal arthritis. Didn’t get that question answered.

    Although I love having the science to understand the phenomena we see (and to substantiate people’s experience of chronic pain!), I hate what I know happens to the unwilling animal participants in many pain studies: “experimental lesioning,” ie, international wounding, ie, torture. My son, who began his career by managing the rodent colony for a lab at the NIH that studied spinal cord injury in animal models, used to tell me about the animals who were lesioned and cried constantly. One rat screamed so piteously that he etherized it without consulting the investigator. Fortunately they did not take action against him. So, while these studies do benefit humans by helping us understand pathological processes and find cures, this happens at enormous cost in suffering for the animals who are subjected to terrible tortures with their only relief coming when they are “sacrificed.”

    I don’t know what the solution is.


  2. Kathy C

    These Studies are fascinating, bu they do little to increase our Understanding of Pain. Few Humans experience the same condition that Rodents do in a lab. It sees to be they don’t even have a basic understanding of Pain. Just like Cancer, there is not going to be a “Magic Bullet,” because there are too many different causes, and underlying problems. “Epigenetic”‘ sounds really Sciency though, it makes these “Studies” sound as if they are meaningful. Once again the meaning of Epigenetics has been distorted to whatever these “Researchers” pre conceived biases are. There won;t be any Clinically significant findings made when Epigenetics is applied through the filter of Bias. The whole idea of Epigenetics has already been distorted, and made to fit into the Researchers world view. Now Epigenetics is merely a catch Phrase or obfuscation, used to peddle Psuedo Science, Backward Biases, and stuff they don’t understand.

    Liked by 1 person

    1. Zyp Czyk Post author

      I like the fact that we didn’t find all the answers by decoding the genome, but only reached the next level of biological complexity. Nature is still way smarter than we are and, for our own protection as a species, I hope it stays that way.



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