Prophylactic topical paeoniflorin prevents mechanical allodynia caused by paclitaxel in mice through adenosine A1 receptors

Abstract

Background: The chemotherapeutic agent paclitaxel (PTX) causes refractory peripheral neuropathy as a side effect. Prophylactic oral administration of the traditional herbal medicine Shakuyakukanzoto containing Paeoniae Radix and Glycyrrhizae Radix prevents the development of PTX-induced mechanical allodynia in mice via peripheral effects, mostly due to Paeoniae Radix. However, the bioactive component responsible for the prevention of PTX-induced neuropathic pain remains unknown.

Purpose: To determine whether a monoterpene glycoside paeoniflorin (PF), which is the principal bioactive constituent of Paeoniae Radix, has inhibitory effects on PTX-induced mechanical allodynia and investigate the underlying mechanisms.

Methods: C57BL/6NCr mice received a single intraperitoneal injection of PTX and then were topically administered PF to the planar surface twice daily for 13 days. Mechanical allodynia was evaluated by the von Frey filament test, peripheral nerve activity was recorded using bipolar electrodes, and demyelination in peripheral nerves was analysed by electron microscopy. Schwann cell line LY-PPB6 pre-treated with PF and then treated with PTX was used to analyse the expression of the transcription factor CHOP, a marker of endoplasmic reticulum (ER) stress, by western blotting.

Results: PTX caused mechanical allodynia and increased both spontaneous and mechanical stimuli-evoked peripheral nerve activities, whereas repetitive topical application of PF significantly attenuated PTX-induced allodynia, suppressed saphenous nerve firing, and inhibited demyelination in the plantar nerve. Moreover, in cultured Schwann cells, PF downregulated PTX-induced expression of CHOP, indicating the inhibition of ER stress. The attenuation of mechanical allodynia in mice and downregulation of CHOP levels in cell cultures was inhibited by adenosine A₁ receptor (A1R) antagonist 8-cyclopentyl-1,3-diprooylxanrhine, suggesting the involvement of A1R in PF-associated analgesic effects.

Conclusion: These results suggest that prophylactic topical application of PF is effective in alleviating PTX-induced mechanical allodynia by protecting sensory nerves from demyelination via activation of the A1R.

Keywords: Adenosine A(1) receptor; Allodynia; Paclitaxel; Paeoniflorin.