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  • Further our study provides the first evidence that


    Further, our study provides the first evidence that zaprinast and kynurenic KW-6002 administration not only prevented the development of thermal and mechanical hypersensitivity but also enhanced morphine antinociceptive properties. Morphine is considered to be one of the most effective analgesic drugs [5,61,62,85,86], however, the changes that lead to the development of neuropathic pain are also responsible for the reduction of its effectiveness in clinical use. The mechanism underlying this phenomenon is still not fully understood. Additionally, in a neuropathic pain model, we demonstrated that the analgesic properties of morphine are lower with neuropathy than in naïve animals [25,87]. For the first time, we have shown in this study that single administration of zaprinast enhances the analgesic activities of morphine. This result is in agreement with previous reports from Yoon et al. [88] and Heo et al. [89], who have also shown that zaprinast enhanced morphine effectiveness in a formalin model. We hypothesize that the increased effectiveness may be due to the ability of zaprinast to inhibit microglial activation in neuropathic pain (Rojewska et al. submitted). It is well known that activated microglia change their gene expression profiles and produce pronociceptive factors (IL-1beta [90]; IL-18 [87]; and many others) that are responsible for the loss of opioid analgesia. It has been found that substances that diminish microglia activation, such as inhibitors (pentoxifylline and minocycline [91]; and antagonists of chemokine receptors (CCR5-maraviroc; [25,92], CCR2- RS504393 [17]; CXCR3-NBI-74330; [57], suppressed the development of neuropathic pain. Recent experimental data supported the potential of combination pharmacotherapy for neuropathic pain. Therapeutic benefits may include greater efficacy, lower dosage and fewer adverse effects. Our data provide new evidence that GPR35 is a promising target for diminishing neuropathic pain and enhancing opioid analgesic effects.
    Author contributions
    Acknowledgments This work was supported by grants from the National Science Centre, Poland: SONATA 2015/17/D/NZ4/02284, OPUS 11 2016/21/B/NZ4/00128 and by statutory funds from the Institute of Pharmacology Polish Academy of Sciences.
    Introduction Patients suffering from neuropathic pain symptoms exhibit ongoing spontaneous and evoked hypersensitivity (Gilron et al., 2015, Truini et al., 2013). Antiepileptics, antidepressants, and opioids are used as analgesic drugs (Hatch et al., 2018, Mika et al., 2013a, Mika et al., 2013b, Nishikawa and Nomoto, 2017); however, adequate treatment of neuropathic pain continues to be challenging because its mechanism is still unclear. The main clinical problem is the weakening of the analgesic effect of opioids in neuropathy, which is why this has been the subject of our research. Based on published results (Rojewska et al., 2016), we postulate that an intensification of the kynurenine pathway occurs as a consequence of nerve injury. The G protein-coupled receptor 35 (GPR35) discovered in 1998 is important for kynurenine pathway activation (Stone et al. (2013); Wang et al. (2006) and has garnered our interest as a potential therapeutic target through its association with a number of diseases that are accompanied by pain (Divorty et al., 2015, Resta et al., 2016). GPR35 is expressed in neuronal and non-neuronal cells in the nervous system and is therefore suggested to be important for nociception (Bischoff, 2004, Kruse et al., 2009, Zhao et al., 2014, Okumura et al., 2004, Wang et al., 2006). GPR35 is a poorly characterized, 7-transmembrane domain G protein-coupled receptor (GPCR) that transmits function via its interaction with Gai/o, Ga13, and β-arrestin (Divorty et al., 2015, Mackenzie et al., 2011, Milligan, 2011, Shore and Reggio, 2015). Preliminary data suggest that GPR35 agonists attenuate inflammatory processes (Divorty et al., 2015), leading to the suggestion that neuropathy may be modulated through this receptor. Zaprinast is the most frequently employed GPR35 agonist; however, zaprinast is also an inhibitor of cyclic GMP-specific phosphodiesterase (Cosi et al., 2011, Taniguchi et al., 2006, Deng et al., 2011, Jenkins et al., 2010, Neetoo-Isseljee et al., 2013, Yang et al., 2010). Some phosphodiesterase inhibitors (pentoxifylline, propentofylline) have beneficial effects on neuropathic/inflammatory pain (Mika et al., 2007, Dorazil-Dudzik et al., 2004, Szczepanik et al., 2004, Wordliczek et al., 2000) and enhance morphine analgesia by modulating glial activation. We hypothesize that the complex mechanism of zaprinast action promises better pain relief. Similar to zaprinast, minocycline has two molecular targets, matrix metallopeptidase 9 and p38 mitogen-activated protein kinase, and has been shown to have beneficial analgesic effects in experimental studies (Niimi et al., 2013, Piao et al., 2006, Rojewska et al., 2014a) and clinical trials (Cunliffe, 1996, Yong et al., 2004).