CONICET | Buscador de Institutos y Recursos Humanos

Background and Aims: Postoperative pain arises from somatic or visceral tissue damage during the course of surgery. It is defined as acute, exhibiting early onset and limited duration, and is considered relevant for appropriate resolution of tissue injury. In most cases, pain symptoms will disappear following resolution. However, excessive acute pain, or its persistence over time is deleterious, not only affecting postsurgical outcomes, also deriving into chronic pain. IMT504 is a non-CpG oligodeoxynucleotide (ODN) that we are extensively characterizing in its anti-allodynic and anti-hyperalgesic properties in rat models of inflammatory and neuropathic pain, upon single subcutaneous (s.c.) administration. In this study, we hypothesize that the pre-emptive administration of IMT504 will prevent the occurrence of mechanical and thermal allodynia in a rat model of postoperative pain. We also hypothesize that opioid-sparing effects could be one additional positive outcome in IMT504-treated rats with post-operative pain. Methods: In male adult Sprague-Dawley rats, we performed the post-incisional pain model, by practicing a surgical cut in the plantar skin and underlying muscle along the axis of the foot, using a scalpel, and followed by suturing of the skin using 5-0 nylon stitches. Rats were divided into groups that include a control group receiving s.c. vehicle (sterile saline solution) and an experimental group receiving s.c. IMT504 (6 mg/kg) 48h and 24 h prior to surgery. Pain-like behaviour was tested by using the von Frey method, to test presence of mechanical allodynia, as well as the Choi test to determine presence of cold allodynia. The von Frey Test was practiced 48 and 24 hours (h) before surgery, at 6, 24 and 72 h after injury, and thereafter each 7 days till completion of a 3 weeks testing period. Thermal hyperalgesia was determined at 72 h after surgery, and once a week till 3 weeks of testing were completed. Finally, the potential opioid-sparing effects of IMT504 were tested in groups of injured rats receiving vehicle or IMT504, and receiving also morphine (1, 3 and 10 mg/kg) at 6 h and 24 h after surgery. In these experiments, mechanical allodynia was determined at 15, 30, 60, 90, 120, 180, 240 min, and at 6h and 24 h after surgery. Results: Single s.c. injections of IMT504, 48 and 24 h prior to surgery led to a statistically significant reduction in mechanical allodynia, evident already 6 h after injury, when compared to vehicle-treated rats. Moreover, while vehicle-treated rats showed clear signs of mechanical allodynia, lasting at least till the first week after injury, and showing signs of full recovery 3 weeks after injury, rats receiving IMT504 exhibited full recovery from 72 h after surgery and onwards. In addition, we observed that IMT504 also reduces cold allodynia, particularly when tested 72 h after injury. Seven days after injury, both vehicle- and IMT504-treated rats returned to basal thermal withdrawal thresholds. Finally, our study also revealed that in IMT504-treated rats, the administration of morphine at 6 or 24 h after injury (when mechanical allodynia is much reduced but not completely reverted in IMT504-treated rats) the ODN exerts opioid-sparing effects, as opposed to such an effect being observed in vehicle treated rats. Thus, in rats receiving IMT504, the administration of 10 mg/kg morphine 6 or 24 h after injury resulted in full restoration of basal withdrawal thresholds during 120 min after injection, followed by progressive reductions in mechanical withdrawal thresholds. Interestingly, IMT504-treated rats receiving 3 mg/kg morphine showed virtually exactly the same duration of effect on pain-like behaviour as observed in IMT504-treated rats receiving 10 mg/kg morphine. The administration of 1 mg/kg morphine in IMT504-treated rats resulted in a shorter lasting opioid effect (between 60 and 90 min duration). Comparisons between vehicle- or IMT504-treated rats receiving different doses of morphine confirmed the opioid-sparing effects of the ODN, particularly when using the 3 mg/kg doses of the opioid. Conclusions: We show for the first time that IMT504 reduces mechanical and cold allodynia in rats with postoperative pain, resulting in a faster recovery of the rats receiving the ODN (up to two weeks, compared to vehicle-treated rats). In addition, we show that during the period of time when IMT504 improves but does not fully prevent pain-like behaviour in rats with skin incision, a third of the effective dose of morphine can be used to efficiently eliminate such a behaviour for a longer period of time than observed in vehicle-treated rats receiving the same morphine dose. This suggests that IMT504 may be useful not only for its own anti-allodynic effects; it could also contribute to reducing the adverse effects typically present in postsurgical patients in need of opioid treatment. Financial Support: PICTO-startup (2016-0091), PICT (2017-0969), Austral University Grant (2019). Ethical Permissions: IACUC-IIMT-17-02

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