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Modulation of the inflammatory response by pre-emptive administration of IMT504 reduces postoperative pain in rats and has opioid-sparing effects

Published:January 24, 2023DOI:https://doi.org/10.1016/j.jpain.2023.01.013

      Highlights

      • Pre-emptive or perioperative IMT504 significantly reduce postsurgical pain
      • Pre-emptive IMT504 results in opioid-sparing effects
      • Pre-emptive IMT504 promotes an anti-inflammatory environment at the incision site and the spleen
      • IMT504 emerges as a potentially attractive drug for the control of postoperative pain

      Abstract

      Despite the available knowledge on underlying mechanisms and the development of several therapeutic strategies, optimal management of postoperative pain remains challenging. This pre-clinical study hypothesizes that, by promoting an anti-inflammatory scenario, pre-emptive administration of IMT504, a non-coding, non-CpG oligodeoxynucleotide with immune modulating properties, will reduce postincisional pain, also facilitating therapeutic opioid-sparing. Male adult Sprague-Dawley rats with unilateral hindpaw skin-muscle incision received pre-emptive (48 h and 24 h prior to surgery) or postoperative (6h after surgery) subcutaneous vehicle (saline) or IMT504. Various groups of rats were prepared for pain-like behaviour analyses, including subgroups receiving morphine or naloxone, as well as for flow-cytometry or quantitative RT-PCR analyses of the spleen and hindpaws (for analysis of inflammatory phenotype). Compared to vehicle-treated rats, pre-emptive IMT504 significantly reduced mechanical allodynia by 6 h after surgery, and accelerated recovery of basal responses from 72 h after surgery and onwards. Cold allodynia was also reduced by IMT504. Postoperative administration of IMT504 resulted in similar positive effects on pain-like behaviour. In IMT504-treated rats, 3 mg/kg morphine resulted in comparable blockade of mechanical allodynia as observed in vehicle-treated rats receiving 10 mg/kg morphine. IMT504 significantly increased hindpaw infiltration of mesenchymal stem cells, CD4+T and B cells, and caused upregulated or downregulated transcript expressions of interleukin-10 and interleukin-1β, respectively. Also, IMT504 treatment targeted the spleen, with upregulated or downregulated transcript expressions, 6 h after incision, of interleukin-10 and interleukin-1β, respectively. Altogether, pre-emptive or postoperative IMT504 provides protection against postincisional pain, through participation of significant immunomodulatory actions, and exhibiting opioid-sparing effects.

      Keywords

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