In this issue of the Scandinavian Journal of Pain, Tianle Gao and coworkers in Zsuzsanna Wiesenfeld-Hallin’s research group at Karolinska Institutet report on the effect of sinomenine to alleviate mechanical hypersensitivity in mice with experimentally-induced rheumatoid arthritis (RA) [1]. Sinomenine is isolated from the climbing plant Sinomenium acutum, and it is used in traditional medicine in Asia for its beneficial effects on auto immune diseases, especially RA [2]. In animal models of arthritis, sinomenine counteracts joint destruction and reduces several signs of inflammation including joint swelling, erythrocyte sedimentation rate, production of antibodies, and secretion of cytokines [3,4]. Besides its antiinflammatory property, sinomenine also reduces pain behaviour in nociceptive, inflammatory, and neuropathic pain models in rodents [5,6,7,8]. Gao and co-workers are now following up the anti-nociceptive effect on inflammation-induced hypersensitivity with further analysis of the effect of sinomenine on mechanical hypersensitivity associated with RA [1]. Pain is a dominating symptom in human RA and the hyperalgesic symptoms often precede the inflammatory signs, and continues after the inflammation subsides. This suggests that it is not only inflammation that is involved in the pathophysiology of pain in RA [9].
Gao and co-workers used the collagen antibody induced arthritis (CAIA) model to induce RA-like symptoms in mice, including joint inflammation and localized mechanical hypersensitivity and/or spread mechanical hypersensitivity. In this model, a cocktail of five antibodies against collagen is injected intravenously after the baseline levels of mechanical sensitivity have been established using von Frey filaments. The immune reaction is later boosted by an intraperitoneal injection of lipopolysaccharide on day 5 after the cocktail injection. This induces profound swelling and redness of the paws and ankles. These symptoms peak at day 15 after the cocktail injection (termed the inflammatory phase). Gao and co-workers studied the effects of sinomenine during the inflammatory phase as well as in the post-inflammatory phase (days 35–54 after the cocktail injection) when the inflammatory signs have subsided but mechanical hypersensitivity continues [1]. They show that sinomenine alleviates mechanical hypersensitivity after single dose treatment. Importantly, the antihypersensitivity effect increases after repeated doses administered during the inflammatory phase as well as during the post-inflammatory phase. They did not observe signs of sedation. As in an earlier study focusing on tolerance development after repeated doses of sinomenine for neuropathic pain [7], they did not observe signs of tolerance in the present study either [1].
Clearly, sinomenine is an interesting substance that promises analgesic and antihyperalgesic effects in human rheumatoid arthritis. Sinomenine is interesting also because it appears to have these effects via mechanisms that are different from those of traditional analgesics. Naloxone did not reverse its effects, demonstrating that sinomenine does not relieve pain and hypersensitivity through the mu-opioid receptors [6]. Other possible mechanisms are via the L-type calcium channel, monoaminergic mechanisms, NMDA-receptors, reduced production of pro-inflammatory cytokines and reactive oxygen species [6,7,8,9,10,11,1213].
Rodent models of nociception and hypersensitivities are notoriously unreliable predictors of analgesic and antihyperalgesic effects in humans [14]. Sinomenine, however, has a reputation in traditional medicine in Asia for helping patients suffering from rheumatoid arthritis [2]. Therefore, it is reasonable to expect that at least some of the findings in studies on rodents by Gao and coworkers [1,6] and other research groups [3] can be found also in humans.
Is it about time now, to proceed to controlled human RA studies?
DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2014.12.003.
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Conflict of interest: The author declares no conflict of interests.
References
[1] Gao T, Shi T, Wiesenfeld-Hallin Z, Svensson CI, Xu XJ. Sinomenine alleviates mechanical hypersensitivity in mice with experimentally-induced rheumatoid arthritis. Scand J Pain 2015;7:9–14.Search in Google Scholar
[2] Zhao XX, Peng C, Zhang H, Qin LP. Sinomenium acutum: a review of chemistry, pharmacology, pharmacokinetics, and clinical use. Pharm Biol 2012;50:1053–61.Search in Google Scholar
[3] Liu L, Buchner E, Beitze D, Schmidt-Weber CB, Kaever V, Emmrich F, Kinne RW. Amelioration of rat experimental arthritides by treatment with the alkaloid sinomenine. Int J Immunopharmacol 1996;18:529–43.Search in Google Scholar
[4] Feng H, Yamaki K, Takano H, Inoue K, Yanagisawa R, Yoshino S. Effect of sinomenine on collagen-induced arthritis in mice. Autoimmunity 2007;40: 532–9.Search in Google Scholar
[5] Wang MH, Chang CK, Cheng JH, Wu HT, Li YX, Cheng JT. Activation of opioid mu-receptor by sinomenine in cell and mice. Neurosci Lett 2008;443:209–12.Search in Google Scholar
[6] Gao T, Hao J, Wiesenfeld-Hallin Z, Wang DQ, Xu XJ. Analgesic effect of sinomenine in rodents after inflammation and nerve injury. Eur J Pharmacol 2013;721:5–11.Search in Google Scholar
[7] Gao T, Shi T, Wang DQ, Wiesenfeld-Hallin Z, Xu XJ. Repeated sinomenine administration alleviates chronic neuropathic pain-like behaviours in rodents without producing tolerance. Scand J Pain 2014;5:249–55.Search in Google Scholar
[8] Pertovaara A. Sinomenine against neuropathic pain hypersensitivity. Scand J Pain 2013;5:248.Search in Google Scholar
[9] Bas DB, Su J, Sandor K, Agalave NM, Lundberg J, Codeluppi S, Baharpoor A, Nandakumar KS, Holmdahl R, Svensson CI. Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis Rheum 2012;64:3886–96.Search in Google Scholar
[10] Wu WN, Wu PF, Chen XL, Zhang Z, Gu J, Yang YJ, Xiong QJ, Ni L, Wang F, Chen JG. Sinomenine protects against is chaemic brain injury: involvement of coinhibition of acid-sensing ion channel 1a and L-type calcium channels. BrJ Pharmacol 2011;164:1445-59.Search in Google Scholar
[11] Zhang MY, Li P, Wang DQ, Niu XH, Wang Y, Wang ZG, Zhang Y, Xu S, Xu XJ. Analgesic effect of sinomenine on SSNI model rats and monoamine neurotransmitters instriatal extracellular fluid. Zhongguo ZhongYao ZaZhi 2013;38:597–604.Search in Google Scholar
[12] Wang Y, Fang Y, Huang W, Zhou X, Wang M, Zhong B, Peng D. Effect of sinomenine on cytokine expression of macrophages and synoviocytes in adjuvant arthritis rats.J Ethnopharmacol 2005;98:37–43.Search in Google Scholar
[13] Qian L, Xu Z, Zhang W, Wilson B, Hong JS, Flood PM. Sinomenine, a natural dextrorotatory morphin analog, is antiinflammatory and neuroprotective through inhibition of microglial NADPHoxidase. J Neuroinflamm 2007;4:23.Search in Google Scholar
[14] Rice ASC, Morland R, Huang W, Currie GL, Sena ES, Macleod MR. Transparency in the reporting of in vivo pre-clinical pain research: the relevance and implications of the ARRIVE (animal research: reporting in vivo experiments) guidelines. Scand J Pain 2013;4:58-62.Search in Google Scholar
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