Korean J Physiol Pharmacol.  2021 Sep;25(5):489-494. 10.4196/kjpp.2021.25.5.489.

5-HT _1A receptors mediate the analgesic effect of rosavin in a mouse model of oxaliplatin-induced peripheral neuropathic pain

• Li D
• Park S
• Lee K
• Jang DS
• Kim SK

• KMID: 2519411
• DOI: http://doi.org/10.4196/kjpp.2021.25.5.489

Abstract

Oxaliplatin, a third-generation platinum derivative, is the mainstay of current antineoplastic medications for advanced colorectal cancer therapy. However, peripheral neuropathic complications, especially cold allodynia, undermine the lifeprolonging outcome of this anti-cancer agent. Rosavin, a phenylpropanoid derived originally from Rhodiola rosea, exhibits a wide range of therapeutic properties. The present study explored whether and how rosavin alleviates oxaliplatin-induced cold hypersensitivity in mice. In the acetone drop test, cold allodynia behavior was observed from days 3 to 5 after a single injection of oxaliplatin (6 mg/kg, i.p.). Cold allodynia was significantly attenuated following rosavin treatment (10 mg/kg, i.p.). Specific endogenous 5-HT depletion by three consecutive pretreatments with parachlorophenylalanine (150 mg/kg/day, i.p.) abolished the analgesic action of rosavin; this effect was not observed following pretreatment with naloxone (opioid receptor antagonist, 10 mg/kg, i.p.). Furthermore, 5-HT_1A receptor antagonist WAY-100635 (0.16 mg/kg, i.p.), but not 5-HT₃ receptor antagonist MDL-72222 (1 mg/kg, i.p.), blocked rosavin-induced analgesia. These results suggest that rosavin may provide a novel approach to alleviate oxaliplatin-induced cold allodynia by recruiting the activity of 5-HT_1A receptors.

Keyword

Cold allodynia; Oxaliplatin; Peripheral neuropathy; Rosavin; Serotonergic

Figure

• 

  Fig. 1 Changes in cold hypersensitivity over time in oxaliplatin and control groups. Animals were randomly administered 5% glucose solution or oxaliplatin (vehicle or OXA, n = 8/group). Mice were subjected to the acetone drop test immediately before the administration on day 0 and from days 1 to 7, respectively (timeline: days 0, 1, 3, 5, and 7). The acetone-elicited responses were counted over 30 s post-applications. Data are expressed as mean ± SEM; *p < 0.05, **p < 0.01, vs. vehicle; by Bonferroni post-hoc test after two-way analysis of variance (ANOVA).

• 

  Fig. 2 Rosavin inhibits cold stimuli‐evoked behavioral hypersensitivity in the oxaliplatin group. Rosavin (1 mg/kg, n = 7; 5 mg/kg, n = 7; 10 mg/kg, n = 8) or vehicle (control, n = 9) was administrated to randomly assigned animals. The acetone drop assay was performed four times, once before application and reassessments at 30, 60, and 120 min post-dosing, respectively (timeline: 0, 30, 60, and 120). Data are expressed as mean ± SEM; *p < 0.05, vs. vehicle; by Bonferroni post-hoc test after two-way analysis of variance (ANOVA).

• 

  Fig. 3 Roles of the serotonergic system in mediating ameliorative effects of rosavin against oxaliplatin-induced cold allodynia in mice. Pretreatment with para-chlorophenylalanine (PCPA) (n = 8) was performed prior to oxaliplatin injection for three consecutive days, and naloxone (n = 6) was administered 15 min before rosavin administration. An equivalent volume of saline was pre-administered to controls (n = 12). Mice presenting neuropathic pain-like behavior were subjected to the acetone drop assay before rosavin treatment (10 mg/kg, Before) and 30 min after administration (After). Data are expressed as mean ± SEM; ***p < 0.001, vs. Before; by Bonferroni post-hoc test after two-way analysis of variance (ANOVA).

• 

  Fig. 4 Effects of 5-HT receptor antagonism on the suppressive properties of rosavin against oxaliplatin-induced cold allodynia in mice. Mice with allodynia were randomly administered with WAY-100635 (n = 6), MDL-72222 (n = 6), or an equivalent volume of the vehicles (saline, the vehicle of WAY-100635, n = 5 or 20% DMSO, the vehicle of MDL-72222, n = 5) 15 min prior to rosavin treatment at days 3 to 5. Cold sensitivity was assessed before antagonist administration (Before) and 30 min after rosavin application (After). Data are expressed as mean ± SEM; **p < 0.01, ***p < 0.001, vs. Before; by Bonferroni post-hoc test after two-way analysis of variance (ANOVA).

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