Korean J Pain.  2021 Jan;34(1):35-46. 10.3344/kjp.2021.34.1.35.

Antinociceptive effects of oleuropein in experimental models of neuropathic pain in male rats

Affiliations
  • 1Department of Anesthesiology, Yidu Central Hospital of Weifang, Weifang, Shandong, China
  • 2Department of Anesthesiology, Hospital T.C.M Affiliated to Southwest Medical University, Luzhou, Sichuan, China
  • 3Orbital Disease and Ophthalmoplasty, Department of Ophthalmological Hospital, The Second Hospital of Jilin, Changchun, Jilin, China
  • 4Department of Anesthesiology, The Lu’an Affiliated Hospital of Anhui Medical University, Lu’an, Anhui Province, China
  • 5Department of Anesthesiology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
  • 6Department of Anesthesiology, Tongji Hospital Affiliated Tongji Medical College, Huazhong Science and Technology University, Wuhan, Hubei, China

Abstract

Background
The present investigation explored the therapeutic actions of oleuropein along with the possible signaling pathway involved in attenuating neuropathic pain in chronic constriction injury (CCI) and vincristine-induced neuropathic pain in male rats.
Methods
Four loose ligatures were placed around the sciatic nerve to induce CCI, and vincristine (50 μg/kg) was injected for 10 days to develop neuropathic pain. The development of cold allodynia, mechanical allodynia, and mechanical hyperalgesia was assessed using different pain-related behavioral tests. The levels of H2S, cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), orexin, and nuclear factor erythroid-2-related factor 2 (Nrf2) were measured in the sciatic nerve.
Results
Treatment with oleuropein for 14 days led to significant amelioration of behavioral manifestations of neuropathic pain in two pain models. Moreover, oleuropein restored both CCI and vincristine-induced decreases in H2S, CSE, CBS, orexin, and Nrf2 levels. Co-administration of suvorexant, an orexin receptor antagonist, significantly counteracted the pain-attenuating actions of oleuropein and Nrf2 levels without modulating H2S, CSE and CBS.
Conclusions
Oleuropein has therapeutic potential to attenuate the pain manifestations in CCI and vincristine-induced neuropathic pain, possibly by restoring the CSE, CBS, and H2S, which may subsequently increase the expression of orexin and Nrf2 to ameliorate behavioral manifestations of pain.

Keyword

Hydrogen Sulfide; Hyperalgesia; Neuralgia; Neuropeptides; NF-E2-Related Factor 2; Nociception; Orexins; Orexin Receptor Antagonists; Polyphenols; Vincristine

Figure

  • Fig. 1 Diagrammatic representation of experimental protocol in (A) chronic constriction injury (CCI) and (B) vincristine model. OLE: oleuropein, Suv: suvorexant, p.o.: per oral, i.p.: intraperitoneal, DMSO: dimethyl sulfoxide, VIN: vincristine-induced neuropathic pain.

  • Fig. 2 Effect of different interventions on the cold allodynia in the acetone drop test in chronic constriction injury (CCI) and vincristine models. Values are in mean ± standard deviation. N = 10, F(14, 135) = 342.5. OLE: oleuropein, Suv: suvorexant, DMSO: dimethyl sulfoxide, VIN: vincristine-induced neuropathic pain. aP < 0.05 vs. sham for CCI, bP < 0.05 vs. CCI, cP < 0.05 vs. OLE (20 mg/kg) in CCI, dP < 0.05 vs. sham for VIN, eP < 0.05 VIN, fP < 0.05 OLE (20 mg/kg) in VIN.

  • Fig. 3 Effect of different interventions on mechanical allodynia in the Von Frey filament test in chronic constriction injury (CCI) and vincristine models. Values are in mean ± standard deviation. N = 10, F(14, 135) = 372.7. OLE: oleuropein, Suv: suvorexant, DMSO: dimethyl sulfoxide, VIN: vincristine-induced neuropathic pain. aP < 0.05 vs. sham for CCI, bP < 0.05 vs. CCI, cP < 0.05 vs. OLE (20 mg/kg) in CCI, dP < 0.05 vs. sham for VIN, eP < 0.05 VIN, fP < 0.05 OLE (20 mg/kg) in VIN.

  • Fig. 4 Effect of different interventions on mechanical hyperalgesia in the pin-prick test in chronic constriction injury (CCI) and vincristine models. Values are in mean ± standard deviation. N = 10, F(14, 135) = 313.8. OLE: oleuropein, Suv: suvorexant, DMSO: dimethyl sulfoxide, VIN: vincristine-induced neuropathic pain. aP < 0.05 vs. sham for CCI, bP < 0.05 vs. CCI, cP < 0.05 vs. OLE (20 mg/kg) in CCI, dP < 0.05 vs. sham for VIN, eP < 0.05 VIN, fP < 0.05 OLE (20 mg/kg) in VIN.

  • Fig. 5 Effect of different interventions on H2S levels in the sciatic nerve in chronic constriction injury (CCI) and vincristine models. Values are in mean ± standard deviation. N = 10, F(14, 135) = 140.5. OLE: oleuropein, Suv: suvorexant, DMSO: dimethyl sulfoxide, VIN: vincristine-induced neuropathic pain. aP < 0.05 vs. sham for CCI, bP < 0.05 vs. CCI, cP < 0.05 vs. sham for VIN, dP < 0.05 VIN.

  • Fig. 6 Effect of different interventions on cystathionine-γ-lyase levels in the sciatic nerve in chronic constriction injury (CCI) and vincristine models. Values are in mean ± standard deviation. N = 10, F(14, 135) = 120.2. OLE: oleuropein, Suv: suvorexant, DMSO: dimethyl sulfoxide, VIN: vincristine-induced neuropathic pain. aP < 0.05 vs. sham for CCI, bP < 0.05 vs. CCI, cP < 0.05 vs. sham for VIN, dP < 0.05 VIN.

  • Fig. 7 Effect of different interventions in cystathionine-β-synthase levels in the sciatic nerve in chronic constriction injury (CCI) and vincristine models. Values are in mean ± standard deviation. N = 10, F(14, 135) = 132.7. OLE: oleuropein, Suv: suvorexant, DMSO: dimethyl sulfoxide, VIN: vincristine-induced neuropathic pain. aP < 0.05 vs. sham for CCI, bP < 0.05 vs. CCI, cP < 0.05 vs. sham for VIN, dP < 0.05 VIN.

  • Fig. 8 Effect of different interventions on orexin levels in the sciatic nerve in chronic constriction injury (CCI) and vincristine models. Values are in mean ± standard deviation. N = 10, F(14, 135) = 154.4. OLE: oleuropein, Suv: suvorexant, DMSO: dimethyl sulfoxide, VIN: vincristine-induced neuropathic pain. aP < 0.05 vs. sham for CCI, bP < 0.05 vs. CCI, cP < 0.05 vs. sham for VIN, dP < 0.05 VIN.

  • Fig. 9 Effect of different interventions on nuclear factor erythroid-2-related factor 2 levels in the sciatic nerve in chronic constriction injury (CCI) and vincristine models. Values are in mean ± standard deviation. N = 10, F(14, 135) = 144.2. OLE: oleuropein, Suv: suvorexant, DMSO: dimethyl sulfoxide, VIN: vincristine-induced neuropathic pain. aP < 0.05 vs. sham for CCI, bP < 0.05 vs. CCI, cP < 0.05 vs. OLE (20 mg/kg) in CCI, dP < 0.05 vs. sham for VIN, eP < 0.05 VIN, fP < 0.05 OLE (20 mg/kg) in VIN.


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