Curcumin-loaded Poly (d,l-lactide-co-glycolide) nanovesicles induce antinociceptive effects after local administration in mice

Both acute and chronic pain are the most widespread medical issue strongly affecting people in terms of health and quality of life. Unlike acute pain, chronic pain is a pathophysiological state arising from the alteration of the peripheral and/or central nervous systems. It is frequently accompanied by the onset of hyperalgesia (increased sensitivity to pain) and allodynia (painful sensation in response to usually innocuous stimuli). Pain is currently treated with two major groups of analgesic drugs, namely non-steroidal anti-inflammatory drugs (NSAIDs) and opioids; their use is associated with important side effects, which include gastrointestinal lesions [1] and nephrotoxicity [2]; in the case of NSAIDs, respiratory depression, tolerance and physical dependence for opioids [3]. For this reason, there is growing interest for the identification of alternative therapeutic strategies. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a yellow polyphenol, diferuloylmethane, extracted from the rhizomes of turmeric (Curcuma longa)[4]. The therapeutic properties of curcumin are well known indeed possesses low intrinsic toxicity along with a wide range of pharmacological activities that include antitumor, anti-amyloid, antioxidant and anti-inflammatory capacities [5]. Antinociceptive properties of curcumin have also been reported in preclinical studies [6], but its poor bioavaibility limits clinical use as analgesic. Polymeric nanoparticle-based drug delivery is being increasingly investigated as a delivery route able to overcome many obstacles associated with the delivery of free drugs. Recently, we investigated the effects of curcumin-loaded PLGA nanovesicles (PLGA-CUR) administered via intravenous (i.v.) or intrathecal (i.t.) routes in several experimental models of pain [7]. We found that i.v. or i.t. routes of administration of PLGA-CUR nanoformulations were effective in reducing the nociception induced by chemical stimuli or after the ligation of the sciatic nerve in mice [7]. In the present study, putative antinociceptive effects induced by CUR and PLGA-CUR after local subcutaneous administration was investigated in two animal models of pain i.e. the formalin test and the hyperalgesia induced by zymosan. We found PLGA-CUR vesicles able to reduce nociception induced by chemical stimuli, whereas CUR alone induced only a transient but not significant antinociceptive effects. These results obtained after acute subcutaneous local PLGA-CUR vesicles administration, further suggest that PLGA-CUR formulation should be developed as a new potential drug in the treatment of pain in humans. _____________________________________ 1. M. Sinha, L. Gautam, P.K. Shukla et al., Mediators Inflamm., 2013, 258209. 2. M. Musu, G. Finco, R. Antonucci et al., Eur. Rev. Med. Pharmacol. Sci, 2011, 15, 1461. 3. R. Benyamin, A.M. Trescot, S. Datta et al., Pain Physician, 2018, S105. 4. S.C. Gupta, G. Kismali, B.B. Aggarwal, Biofactors, 2013, 39, 2. 5. S. Sharma, S.K. Kulkarni, J.N. Agrewala et al., Eur. J. Pharmacol., 2006, 536, 256. 6. L. Allegri, F. Rosignolo,C. Mio et al., J. Cancer Res. Clin. Oncol. 2018, 144, 285. 7. S. Pieretti, A.P. Ranjan, A. Di Giannuario et al., Colloids Surf B Biointerfaces, 2017, 158, 379.