Suyong Kim

Oxaliplatin is a chemotherapy drug that can induce severe acute neuropathy in patients within hours of treatment. In our previous study, 10 mg/kg [6]-shogaol (i.p.) significantly alleviated cold and mechanical allodynia induced by a 6 mg/kg oxaliplatin injection (i.p.); however, the precise serotonin-modulatory effect has not been investigated. In this study, we showed that intrathecal injections of NAN-190 (5-HT_1A receptor antagonist, 1 µg) and MDL-72222 (5-HT₃ receptor antagonist, 15 µg), but not ketanserin (5-HT_2A receptor antagonist, 1 µg), significantly blocked the analgesic effect of [6]-shogaol (10 mg/kg, i.p.). Furthermore, the gene expression of the serotonin-synthesizing enzyme tryptophan hydroxylase 2 (TPH2) and serotonin levels in the spinal cord and serum were significantly downregulated (p < 0.0001 and p = 0.0002) and upregulated (p = 0.0298 and p = 0.0099) after oxaliplatin and [6]-shogaol administration, respectively. Moreover, both the gene and protein expression of the spinal serotonin receptors 5-HT_1A and 5-HT₃ significantly increased after [6]-shogaol injections (p < 0.0001). Finally, intrathecal injections of both receptor agonists (8-OH-DPAT; 5-HT_1A receptor agonist, 10 µg and m-CPBG; 5-HT₃ receptor agonist, 15 µg) mimicked the effects of [6]-shogaol in oxaliplatin-injected mice. Taken together, these results demonstrate that [6]-shogaol attenuates oxaliplatin-induced neuropathic pain by modulating the spinal serotoninergic system.

Zingiber officinale Roscoe (ginger) has long been used as an herbal medicine to treat various diseases, and its main sub-components, [6]-gingerol and [6]-shogaol, were also reported to have anti-inflammatory, anti-oxidant, and anti-tumor effects. However, their effects on various types of pain and their underlying mechanisms of action have not been clearly analyzed and understood yet. Thus, in this review, by analyzing 16 studies that used Z. officinale, [6]-gingerol, and [6]-shogaol on mechanical, spontaneous and thermal pain, their effects and mechanisms of action have been analyzed. Pain was induced by either nerve injury or chemical injections in rodents. Nine studies analyzed the analgesic effect of Z. officinale, and four and three studies focused on [6]-gingerol and [6]-shogaol, respectively. Seven papers have demonstrated the underlying mechanism of action of their analgesic effects. Studies have focused on the spinal cord and one on the dorsal root ganglion (DRG) neurons. Involvement and change in the function of serotonergic receptors (5-HT_1A, _B, _D, and _5A), transient receptor potential vanilloid 1 (TRPV1), N-methyl-D-aspartate (NMDA) receptors, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), histone deacetylase 1 (HDAC1), voltage-gated sodium channel 1.8 (Na_v1.8), substance P (SP), and sciatic nerve’s morphology have been observed.

Although oxaliplatin is a well-known anti-cancer agent used for the treatment of colorectal cancer, treated patients often experience acute cold and mechanical allodynia as side effects. Unfortunately, no optimal treatment has been developed yet. In this study, [6]-shogaol (10 mg/kg, i.p.), which is one of the major bioactive components of Zingiber officinale roscoe (Z. officinale), significantly alleviated allodynia induced by oxaliplatin (6 mg/kg, i.p.) injection. Cold and mechanical allodynia were assessed by acetone drop and von Frey filament tests, respectively. The analgesic effect of [6]-shogaol was blocked by the intrathecal injection of 5-HT1A, 5-HT3, and GABAB receptor antagonists, NAN-190 (1 μg), MDL-72222 (15 μg), and CGP 55845 (10 μg), respectively. Furthermore, oxaliplatin injection lowered the GABA concentration in the superficial laminae of the spinal dorsal horn, whereas [6]-shogaol injection significantly elevated it. The GAD (glutamic acid decarboxylase) 65 concentration also increased after [6]-shogaol administration. However, pre-treatment of NAN-190 completely inhibited the increased GABA induced by [6]-shogaol in the spinal dorsal horn, whereas MDL-72222 partially blocked the effect. Altogether, these results suggest that [6]-shogaol could attenuate oxaliplatin-induced cold and mechanical allodynia through 5-HT_1A and 5-HT₃ receptor antagonists located in the GABAergic neurons in the spinal dorsal horn in mice.