Background & Aims
Neuropathic pain management faces challenges due to limited understanding of its mechanisms. Microglia, the immune cells of central nervous system, and the P2Y12 receptor on them [2, 3] play pivotal roles in neuropathic pain. Inhibiting microglial activation, particularly via P2Y12 receptors, is a current focus [5]. Existing P2Y12 antagonists, designed for anti-clotting effects, offer a potential avenue for pain relief [1]. We employed oral ticagrelor to target microglial P2Y12 receptors in a rat model of partial sciatic nerve ligation, evaluating effects on mechanical allodynia, locomotor activity, exploratory behaviour, and memory. This research aims to advance insights into microglial involvement in neuropathic pain and explore ticagrelor’s potential for novel treatment strategies.
Methods
Adult male Sprague Dawley rats were assigned to four groups (Sham, PSNL, Vehicle, and Ticagrelor), each with six rats. The PSNL, Vehicle, and Ticagrelor groups underwent partial sciatic nerve ligation surgery [4], while the Sham group underwent a sham procedure. The study extended for 14 days. The Vehicle group received oral 25% DMSO, and the Ticagrelor group was orally administered ticagrelor (3mg/kg) from post-op day 3 until sacrifice. Behavioural tests included the von Frey filament test on post-op days 7 and 14, Open Field Test on the day of sacrifice, and Novel Object Recognition on two days before sacrifice. Rats were sacrificed on day 14 via chloroform anaesthesia and trans-cardial perfusion. Lumbar spinal cord segments (L4, L5) were obtained, cut into 20-micron sections, and processed for IbA1 immunohistochemistry. IbA1-positive microglial cells were quantified using ImageJ on both ipsilateral and contralateral spinal horns.
Results
Significant paw threshold reduction occurred in the PSNL and Vehicle groups on post-opdays 7 and 14, peaking on day 14. DMSO provided no protection. In the Ticagrelor group, paw thresholds were comparable to Sham, indicating that ticagrelor mitigated the pain.
PSNL and Vehicle groups displayed altered exploratory and locomotor behaviour, avoiding central zones. Ticagrelor rats resembled Sham behaviour, suggesting a preservation of normal exploratory and locomotor patterns. This behaviour in the PSNL and Vehicle groups may be pain-induced, causing rats to avoid movement to minimise discomfort.
No significant recognition index differences were found among groups, indicating no memory disturbances. No conclusive comments can be made on ticagrelor’s impact on memory loss.
IbA1-positive microglial cell counts in PSNL and Vehicle groups surged on the ipsilateral side but remained similar to Sham in the Ticagrelor group. This implies ticagrelor may inhibit microglial activation.
Conclusions
In conclusion, our study on ticagrelor in rat neuropathic pain model unveils promising neuroprotective effects. Ticagrelor significantly reduces paw threshold levels, preserving normal exploratory and locomotor behaviours. The Ticagrelor group displays behaviour akin to the Sham group, suggesting its potential in maintaining normalcy amid neuropathic conditions. Notably, microglial inhibition by ticagrelor adds a cellular dimension, emphasizing its role in modulating neuroinflammation. While further investigations are essential, our findings position ticagrelor as a promising candidate for neuropathic pain relief, providing insights into its impact on both behaviour and cellular mechanisms.
References
1.Baqi Y, Müller CE. Antithrombotic P2Y12 receptor antagonists: recent developments in drug discovery. Drug Discov Today. 2019 Jan;24(1):325-333. doi: 10.1016/j.drudis.2018.09.021. Epub 2018 Oct 3. PMID: 30291899.
2.Horváth G, Gölöncsér F, Csölle C, Király K, Andó RD, Baranyi M, Koványi B, Máté Z, Hoffmann K, Algaier I, Baqi Y, Müller CE, Von Kügelgen I, Sperlágh B. Central P2Y12 receptor blockade alleviates inflammatory and neuropathic pain and cytokine production in rodents. Neurobiol Dis. 2014 Oct;70:162-78. Doi: 10.1016/j.nbd.2014.06.011. Epub 2014 Jun 25. PMID: 24971933; PMCID: PMC4148180.
3.Ming LG, Hu DX, Zuo C, Zhang WJ. G protein-coupled P2Y12 receptor is involved in the progression of neuropathic pain. Biomed Pharmacother. 2023 Jun;162:114713. doi: 10.1016/j.biopha.2023.114713. Epub 2023 Apr 20. PMID: 37084563.
4.Seltzer Z, Dubner R, Shir Y. A novel behaviour model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain. 1990 Nov;43(2):205-218. Doi: 10.1016/0304-3959(90)91074-S. PMID: 1982347.
5.Yu T, Zhang X, Shi H, Tian J, Sun L, Hu X, Cui W, Du D. P2Y12 regulates microglia activation and excitatory synaptic transmission in spinal lamina II neurons during neuropathic pain in rodents. Cell Death Dis. 2019 Feb 18;10(3):165. doi: 10.1038/s41419-019-1425-4. PMID: 30778044; PMCID: PMC6379416.
Presenting Author
S Kamalesh
Poster Authors
S Kamalesh
MD
All India Institute of Medical Sciences
Lead Author
M Bishnoi
Santosh Medical College, Ghaziabad (U.P.)
Lead Author
S B Ray
All India Institute of Medical Sciences
Lead Author
Saroj Kaler Jhajhria
All India Institute of Medical Sciences, New Delhi
Lead Author
Topics
- Mechanisms: Biological-Systems (Physiology/Anatomy)