Background & Aims
Chronic postsurgical pain (CPSP) is a significant complication following surgical procedures. CPSP, defined as pain persisting for at least three months after surgery, has a prevalence ranging from 5% to 85%, depending on the surgical type (1). A previous study from our group demonstrated that the administration of neutrophils or S100A8/A9 proteins, released by neutrophils, effectively prevents dexamethasone-induced (DEXA) prolongation of inflammatory or neuropathic pain (2). In this study we aim to investigate the potential of agonists for prostaglandin (PG) receptors PTGIR and PTGER4 in preventing prolongation of pain in a CPSP mouse model, based on the observation that activation of PTGIR and PTGER4 receptors upregulate S100A8/A9 expression in human myeloid cells through the PKA-STAT3 pathway (3).
Methods
CPSP model: CD-1 mice underwent a plantar incision in the right hind paw following the Cowie and Stucky protocol (4). Subcutaneous injections of either DEXA (0.5 mg/kg/day) or saline were administered from the day before surgery to day 6 post-surgery.
Drug administration: Oral administration of PTGIR agonists (beraprost or treprostinil, 100 µg/kg/day), PTGER4 agonist (misoprostol, 200 µg/kg/day), or saline were given from day 5 to 8 post-surgery.
Mechanical allodynia: Mechanical sensitivity on the ipsilateral paw was assessed using von Frey filaments. The tests were performed on days 1, 7, 14, 21, and bi-weekly until day 72. Withdrawal thresholds were calculated using the up-down method of Dixon (5).
Results
Mice treated with saline recovered after incisional injury in two weeks, while those treated with DEXA developed prolonged hyperalgesia. The PTGIR and PTGER4 agonists (beraprost, treprostinil, and misoprostol) prevented long-lasting DEXA-induced hyperalgesia, and mice recovered after only one week. However, mice not treated with DEXA but only PG agonists after incisional surgery also exhibited hypersensitivity for up to one month after plantar incision.
Conclusions
PTGIR and PTGER4 agonists can prevent the prolonged hyperalgesia induced by DEXA in plantar incision surgery (a novel model of CPSP), suggesting a potential therapeutic approach to alleviate CPSP. This effect is likely mediated by S100A8/A9 up-regulation through the PKA-STAT3 pathway in myeloid cells, although this remains to be demonstrated.
References
1.Thapa P, Euasobhon P. Chronic postsurgical pain: current evidence for prevention and management. Korean J Pain. 2018;31(3):155-73.
2.Parisien M, Lima LV, Dagostino C, El-Hachem N, Drury GL, Grant AV, et al. Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Sci Transl Med. 2022;14(644):eabj9954.
3.Karaky M, Boucher G, Mola S, Foisy S, Beauchamp C, Rivard ME, et al. Prostaglandins and calprotectin are genetically and functionally linked to the Inflammatory Bowel Diseases. PLoS Genet. 2022;18(9):e1010189.
4.Cowie AM, Stucky CL. A Mouse Model of Postoperative Pain. Bio Protoc. 2019;9(2).
5.Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55-63.
Presenting Author
Mohamad Karaky
Poster Authors
Mohamad Karaky
PhD
McGill University
Lead Author
Lucas V. Lima
PhD
McGill University
Lead Author
Anahita Oveisi
MSc
McGill University
Lead Author
Jeffrey Mogil
McGill University
Lead Author
Luda Diatchenko
McGill University
Lead Author
Francesca Montagna
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Post-surgical/Post-traumatic Chronic Pain