Antiallodynic and anti-inflammatory effects of intrathecal R-PIA in a rat model of vincristine-induced peripheral neuropathy

Abstract

Background: Studies investigating the correlation between spinal adenosine A1 receptors and vincristine-induced peripheral neuropathy (VIPN) are limited. This study explored the role of intrathecal N6-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA) in the rat model of VIPN.

Methods: Vincristine (100 μg/kg) was intraperitoneally administered for 10 days (two 5-day cycles with a 2-day pause) and VIPN was induced in rats. Pain was assessed by evaluating mechanical hyperalgesia, mechanical dynamic allodynia, thermal hyperalgesia, cold allodynia, and mechanical static allodynia. Biochemically, tumor necrosis factor-alpha (TNF-α) level and myeloperoxidase (MPO) activity were measured in the tissue from beneath the sciatic nerve.

Results: Vincristine administration resulted in the development of cold allodynia, mechanical hyperalgesia, thermal hyperalgesia, mechanical dynamic allodynia, and mechanical static allodynia. Intrathecally administered R-PIA (1.0 and 3.0 μg/10 μl) reversed vincristine-induced neuropathic pain (cold and mechanical static allodynia). The attenuating effect peaked 15 min after intrathecal administration of R-PIA after which it decreased until 180 min. However, pretreatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10 μg/10 μl) 15 min before intrathecal R-PIA administration significantly attenuated the antiallodynic effect of R-PIA. This antiallodynic effect of intrathecal R-PIA may be mediated through adenosine A1 receptors in the spinal cord. Intrathecally administered R-PIA also attenuated vincristine-induced increases in TNF-α level and MPO activity. However, pretreatment with intrathecal DPCPX significantly reversed this attenuation.

Conclusions: These results suggest that intrathecally administered R-PIA attenuates cold and mechanical static allodynia in a rat model of VIPN, partially due to its anti-inflammatory actions.

Keywords: Adenosine; DPCPX; Neuropathy; R-PIA; Receptor; Vincristine..

Fig. 1.

Diagrammatic representation of the experimental protocol. DPCPX: 1,3-dipropyl-8-cyclopentylxanthine = adenosine A1 receptor antagonist; R-PIA: N6-(2-phenylisopropyl)-adenosine R-(-)isomer = adenosine A1 receptor agonist.

Fig. 2.

Behavioral examinations following vincristine administration. (A) Cold allodynia assessed by the acetone drop test, (B) Mechanical hyperalgesia assessed by the pin-prick test, (C) Thermal hyperalgesia assessed by the hot plate test, (D) Mechanical dynamic allodynia assessed by the paint brush test, (E) Mechanical static allodynia assessed by the von Frey filament test. Values are presented as mean ± standard error of mean, n = 6 rats per group. One-way ANOVA followed by Tukey’s post hoc test. *P < 0.05 vs. behavioral examination on day 0, ^†P < 0.05 vs. behavioral examination on day 14.

Fig. 3.

The effect of different pharmacological interventions on TNF-α level (A) and myeloperoxidase activity (B) in tissue from beneath the sciatic nerve. Peripheral neuropathy was induced by the administration of vincristine (100 μg/kg, i.p.) for 10 days. On the 28th day, saline or DPCPX (10 μg/10 μl) was intrathecally administered 15 min before intrathecal R-PIA administration (1.0 μg/10 μl or 3.0 μg/10 μl). Values are presented as mean ± standard error of mean, n = 6 rats per group. One-way ANOVA followed by Tukey’s post hoc test. *P < 0.05 vs. normal control group, ^†P < 0.05 vs. vincristine control group, ^‡P < 0.05 vs. R-PIA 1.0 μg/10 μl group, ^§P < 0.05 vs. R-PIA 3.0 μg/10 μl group. DPCPX: 1,3-dipropyl-8-cyclopentylxanthine = adenosine A1 receptor antagonist; R-PIA: N6-(2-phenylisopropyl)-adenosine R-(-)isomer = adenosine A1 receptor agonist.