Systemic and local anti‐nociceptive effects of simvastatin in the rat formalin assay: Role of peroxisome proliferator‐activated receptor γ and nitric oxide

Abstract

This study aimed to determine the potential systemic and local anti-nociceptive effects of simvastatin (SIM) and the possible role of peroxisome proliferator-activated receptor gamma (PPARγ) and nitric oxide (NO) pathways using a formalin assay in rats. After allocation, rats were intraplantarly (i.pl.) treated with formalin solution (2.5%) and the flinching behaviors were recorded for 5 min (phase 1) and 15-60 min (phase 2). SIM was given intraperitoneally (i.p.) and i.pl. 30 and 20 min before test, respectively. Intraperitoneal administration of SIM attenuated the flinching number during both phases of the test. This effect of i.p. SIM was significantly reduced by -NAME (NO synthase blocker, i.p.), but was augmented by -arginine (NO precursor, i.p.) during both phases of the formalin assay. Moreover, the antinociception caused by i.p. SIM was blocked by GW-9662 (PPARγ antagonist) at dose 2 mg/kg (i.p.). In another experiment, concurrent ip administration of non-effective dose of simvastatin (5 mg/kg) with pioglitazone (PPARγ agonist; 10, 20 mg/kg) produced antinociception. However, pre-treatment with i.p. GW-9662 inhibited the enhanced antinociceptive effect of pioglitazone on SIM during the phase 2 of formalin assay. Results also showed that i.pl. SIM alone had no anti-nociceptive effects. However, significant anti-nociception was observed when SIM (i.pl.) co-administered with non-effective dose of pioglitazone. Moreover, the enhanced effect was antagonized by pre-treatment with i.pl. GW-9662. Our data suggest that SIM produced antinociception through systemic but not local route of administration in rats. Moreover, the antinociceptive effect of SIM is partly mediated through PPARγ receptors and NO pathway. © 2017 Wiley Periodicals, Inc.

Involvement of the L-arginine/Nitric Oxide/Cyclic GMP/KATP Channel Pathway and PPARγ Receptors in the Peripheral Antinociceptive Effect of Carbamazepine

“…tissue of rat that can produce anti-inflammation by PPARγ agonists [36]. Moreover, we previously reported that the role of PPARγ receptors in the antinociceptive effects of some drugs [17,18]. On the other hand, Turpin et al (2013) indicated that carbamazepine may alter cell metabolism through PPARγ receptors in mice cells [19].…”

“…Doses and drug administration schedules (▶Fig. 1) were selected based on previous reports and also our experience in the laboratory [7,11,17,20].…”

“…Peroxisome proliferator-activated receptors (PPARs) are liganddependent activated nuclear receptors which widely expressed in adipose tissue, immune cells, neurons, and glia of the peripheral nervous system, and modulate the inflammatory process and pain [16]. In previous reports, we showed the role of PPARγ receptors in animal models of pain [17,18]. On the other hand, Turpin et al (2013) indicated that carbamazepine may alter adipose tissue development and metabolism through PPARγ receptors in mice cells [19].…”

Evaluation of cebranopadol, a dually acting nociceptin/orphanin FQ and opioid receptor agonist in mouse models of acute, tonic, and chemotherapy-induced neuropathic pain

“…We used two protocols of its administration: the first one which utilized this drug alone, and the second one in which cebranopadol was used in combination with simvastatin. Available data show potential effectiveness of simvastatin in several animal models of pain (Shi et al 2011 ; Miranda et al 2011 ; Chen et al 2013 ; Mansouri et al 2017 ), including inflammatory (Chen et al 2013 ) and neuropathic pain models (Shi et al 2011 ). First, in the previous studies (Bhalla et al 2015 ), simvastatin effectively reversed vincristine-induced neuropathic pain by anti-inflammatory effects and it was able to attenuate vincristine-induced increase in myeloperoxidase activity.…”