The intrathecal administration of losartan, an AT1 receptor antagonist, produces an antinociceptive effect through the inhibiton of p38 MAPK phosphorylation in the mouse formalin test

Background Although spinal cannabinoid receptor agonist (WIN 55,212-2) has been shown to encounter various models of pain, the role of two subtypes of cannabinoid receptor for the antinociceptive effect of cannabinoids has not been investigated at the spinal level. Spinal alpha 2 receptor agonist (clonidine) and cholinesterase inhibitor (neostigmine) are also active in the modulation of nociception. The authors examined the properties of drug interaction after coadministration of WIN 55,212-2-clonidine, and intrathecal WIN 55,212-2-neostigmine, and further clarified the role of cannabinoid 1 and 2 receptors in cannabinoid-induced antinociception at the spinal level. Methods Catheters were inserted into the intrathecal space of male Sprague-Dawley rats, and 50 microl of 5% formalin solution was injected into the hind paw to evoke the pain. Isobolographic analysis was used for evaluation of pharmacologic interaction. Results Intrathecal 55,212-2, clonidine, and neostigmine dose-dependently suppressed the flinching observed during phase 1 and 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of WIN 55,212-2-clonidine or WIN 55,212-2-neostigmine mixture in both phases. The antinociceptive effect of WIN 55,212-2 was antagonized by cannabinoid 1 receptor antagonist (AM 251) but not by cannabinoid 2 receptor antagonist (AM 630). No antinociceptive effect was seen after intrathecal administration of cannabinoid 2 receptor agonist (JWH 133). Conclusions Intrathecal 55,212-2, clonidine, and neostigmine attenuate the facilitated state and acute pain. WIN 55,212-2 interacts synergistically with either clonidine or neostigmine. The antinociception of WIN 55,212-2 is mediated through the cannabinoid 1 receptor, but not the cannabinoid 2 receptor, at the spinal level.

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Antinociceptive effects of intrathecal cimifugin treatment: a preliminary rat study based on formalin test

Anesthesia and Pain Medicine ◽

10.17085/apm.20032 ◽

2020 ◽

Vol 15 (4) ◽

pp. 478-485

Author(s):

Hyun Young Lee ◽

Young Joon Ki ◽

Su Yeong Park ◽

Soo Yeon Cho ◽

Jinyoung Seo ◽

...

Keyword(s):

Analgesic Effect ◽

Formalin Test ◽

Phase 1 ◽

Antinociceptive Effect ◽

Intrathecal Administration ◽

Phase 2 ◽

Sprague Dawley ◽

Antinociceptive Effects ◽

Saposhnikovia Divaricata ◽

Rat Study

Background: Cimifugin is one of the components of the root of Saposhnikovia divaricata. The extract derived from S. divaricata is traditionally used as an analgesic. This study was conducted to evaluate the analgesic effect of intrathecal cimifugin in the formalin test.Methods: Male Sprague–Dawley rats (n = 20) were randomized into four groups for intrathecal administration of 70% dimethylsulfoxide and various doses of cimifugin (100 μg, 300 μg, and 1,000 μg). The typical flinch response after the injection of 5% formalin into the hind paw was assessed in two distinct phases: phase 1 until 10 min, and phase 2 from 10 min to 60 min. ED50 values were calculated via linear regression.Results: Intrathecal cimifugin significantly reduced the flinch response in both phases of the formalin test. Significant antinociceptive effects of cimifugin were found with the dose of 300 μg in phase 1 and the dose of 100 μg in phase 2. The ED50 value (95% confidence intervals) of intrathecal cimifugin was 696.1 (360.8–1,342.8) μg during phase 1 and 1,242.8 (42.0–48,292.5) μg during phase 2.Conclusions: Intrathecal cimifugin has an antinociceptive effect against formalin-induced pain. Cimifugin has an anti-inflammatory effect at low concentrations, and non-inflammatory analgesic effect at higher concentrations.

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