The µ-δ opioid heteromer masks latent pain sensitization in neuropathic and inflammatory pain in male and female mice

Chronic pain has been linked to numerous physical and mental conditions and contributes to high health care costs and lost productivity. it is not surprising that opioid analgesics are now the most commonly prescribed class of medications in many countries.

Chronic pain has an episodic nature, which has been studied in the rodent model of latent pain sensitization. Following the remission of pain, the activation of opioid receptors opposes central sensitization. When the opioid receptor antagonism reinstates pain hypersensitivity, latent pain sensitization gets unmasked. In previous studies, the focus has been on male rodents and inflammatory pain. It is not yet known if models of chemotherapy-induced neuropathic pain in female and male mice experience latent pain sensitization.

To answer this question, Dr. Kufreobong Inyang and Dr. Geoffroy Laumet from the Michigan State University together with Professor Susan George from the University of Toronto explored the effects of μ- and δ- opioid receptors on latent pain sensitization in their mouse model of chemotherapy-induced neuropathic pain in both sexes. Their results showed that μ-and δ-opioid receptors form a heteromer that plays an important role in the remission of pain. The original research article is now published in the Journal Brain Research.

The authors observed that mice treated with cisplatin to induce neuropathic pain became hypersensitive and both sexes of mice had peak of hypersensitivity on day 4. After 3 weeks when they were deemed to be in remission, the administration of naltrexone reinstated the pain hypersensitivity in cisplatin-treated mice in both sexes at 30 and 60 min. However, in mice treated with phosphate-buffered saline as a control, the administration of naltrexone had no effect. In cisplatin-treated mice of both sexes, naltrindole injection after remission once pain sensitivity threshold was back to normal also reinstated pain hypersensitivity 30- and 60-min post-injection remission. In contrast, the pain threshold in phosphate-buffered saline-treated mice was not affected by naltrindole administration. “This is very intriguing because it shows that mice that have experienced pain respond to pharmacological treatment differently than mice that had not experienced pain” explains Laumet.

Moreover, the research team noticed that the individual blockade of δ opioid receptors and µ opioid receptors unmasked latent pain sensitivity. When the µ-δ opioid receptor heteromer was disrupted, the team found that it resulted in the reinstatement of pain hypersensitivity in mice of both sexes treated with cisplatin, but had no effect on phosphate-buffered saline-treated mice. This led to the conclusion that the µ-δ opioid heteromer contributed to the maintenance of remission in both sexes. In addition, in post-surgical mice, µ-δ opioid heteromer disruption induced pain hypersensitivity, whereas the administration of the control scramble peptide had no effect on mechanical sensitivity. From this data, the team inferred that the µ-δ opioid heteromer contributed to remission of postsurgical pain maintenance in both sexes. Laumet says that “our study provides new insight into the multi-level roles of opioid receptors in analgesia”.

The new finding from this study is that following the remission from cisplatin-induced neuropathic pain in both male and female mice, latent pain sensitization occurs and the maintenance of remission is supported by the µ-δ opioid heteromer. Recently, consider sex as an important variable in biomedical research including pain research, to ensure that studies cover the range of possibilities rather than gleaning results from a single population. A major initiative from the US National Institutes of Health (NIH) made it a requirement for grant applicants to justify their choice of the sex of animals used in experiments. This initiative is expected to make pain therapeutics developed in the future are relevant to both men and women who suffer from chronic pain.

In summary, through this study the authors have demonstrated that latent pain sensitization occurs in chronic pain models with different etiologies and in both sexes. They have also shown that the µ-δ opioid heteromer plays a critical role in the maintenance of remission of both cisplatin-induced neuropathic pain and postsurgical pain and in both sexes. Based on these findings they have suggested that latent pain sensitization can be generalized to almost all chronic pain conditions. In addition to findings from other studies, this study confirmed the µ-δ opioid heteromer as a potential target for the prevention of recurrent pain and treatment of persistent pain conditions.