Epigenetic changes to pain sensitivity an analgesic tolerance induced by chronic pre-operative opioid abuse

Opioids are commonly used to treat acute and chronic pain despite the negative side-effects that are associated with chronic opioid use, such as analgesic tolerance and increased sensitivity to pain (opioid-induced hyperalgesia, or OIH). Clinical observations indicate that patients who use opioids chronically prior to surgery have worse long-term functional outcomes than patients who do not. In April 2016, a group led by Dr. J. David Clark (Stanford University and the Veterans Affairs Palo Alto Health Care System) reported in the journal Molecular Pain that chronic opioid exposure induces epigenetic changes in the spinal cord that  enhance pain severity and duration after surgery. The discovery of these changes provide possible targets for therapeutic development aimed at decreasing opioid-induced hypersensitivity and analgesic tolerance that is confounded by surgical procedures in chronic opioid users.

Chronic opioid exposure prior to surgery exacerbates OIH and opioid tolerance

To model chronic morphine exposure, male C57BL/6J mice (000664) received daily morphine treatments following an escalating-dose schedule over 4 days. After the final dose, the mice received a hindpaw plantar incision, and mechanical allodynia – a painful sensation caused by innocuous stimuli such as light touch – was evaluated. Chronic morphine treatment or hindpaw incision, resulted in mechanical allodynia, however, mice that received both chronic morphine and hindpaw incision had significantly greater allodynic responses compared to the other groups. Additionally, the analgesic effect of post-operative morphine treatment was significantly reduced in the group that received the chronic morphine treatment prior to surgery compared with the group that did not, indicating that pre-operatively-treated mice had developed tolerance developed.

Opioid exposure and surgical incision interact through spinal epigenetic processes to enhance the expression of brain-derived neurotrophic factor (Bdnf) and prodynorphin (Pdyn)

Epigenetic alterations to gene expression do not rely on changes in the genomic sequence; they occur  without genetic mutations. Lysine residue acetylation in histone proteins in spinal cord cells is an epigenetic mechanism that contributes to nociceptive sensitization, tolerance to opioid analgesia and OIH after surgical incision. Early studies of post-operative pain demonstrated that histone acetylation enhances both brain-derived neurotrophic factor (Bdnf) and prodynorphin (Pdyn) expression in spinal cord tissues. In the present study, Dr. Clark's group showed that Bdnf and Pdyn expression were enhanced in mice that received both chronic pre-operative morphine administration and surgical incision, and the increase in mRNA expression coincided with increased BDNF and PDYN protein levels.  Further, histone H3K9 proteins associated with the Bdnf and Pdyn promotor regions showed more pronounced acetylation in the pre-operative morphine-treated animals that received incisions compared to other groups.

A functional link between enhanced Bdnf and Pdyn expression and analgesic tolerance and OIH

To investigate whether the enhanced Bdnf and Pdyn gene and protein expression observed in the preoperative, morphine-treated mice was linked functionally with heightened analgesic tolerance and OIH, mice were treated with antagonists to Bdnf and Pdyn signaling. Both selective tropomyosin-related kinase B (ANA-12) and κ-opioid receptor antagonists (nor-binaltorphimine; norBNI) reduced OIH and improved the efficacy of opioid analgesia in mice that were exposed to chronic opioid administration preoperatively. Additionally, co-administration of anacardic acid, a histone acetyltransferase inhibitor, with pre-operative morphine prevented OIH and opioid-induced tolerance observed in the mice that did not receive the inhibitor.

Taken together, these data show that chronic opioid exposure induces epigenetic changes that alter nociceptive signaling. Additionally, the data suggests that therapies that target the BDNF-TrkB and dynorphin-KOR signaling pathways might combat the post-operative increases to pain sensitivity and analgesic tolerance that are associated with pre-operative chronic opioid use.


Sahbaie P, Liang D-Y, Shi X-Y, Sun Y, Clark JD. 2016. Epigenetic regulation of spinal cord gene expression contributes to enhanced postoperative pain and analgesic tolerance subsequent to continuous opioid exposure. Mol Pain. 12: 1744806916641950. PMID: 27094549.