Central antinociceptive effect of tapentadol is increased by nitric oxide synthase inhibitors

Abstract

Nitric oxide synthases (NOSs) have been shown to participate in the mechanism of the antinociceptive action of tapentadol. The results obtained in this study indicate that tapentadol administered intrathecally at a range of doses (30-100 µg) increased nociceptive thresholds in the Randall-Selitto and tail-flick tests in rats; however, this effect was significant only for the higher doses. After intracerebroventricular administration of tapentadol at the same dose range, an antinociceptive effect was observed only in response to mechanical stimuli. In coadministration studies, L-N-nitro arginine (L-NOArg) - a nonselective NOS inhibitor as well as selective inhibitors: 7-Nitroindazole (7-NI), L-N(1-iminoethyl)lysine (L-NIL) or N-(1-iminoethyl)-L-ornithine (L-NIO) for the respective neuronal, inducible, and endothelial NOSs enhanced the antinociceptive activity of intrathecally administered tapentadol in the Randall-Selitto test and to a lesser extent in the tail-flick test. A similar, although less pronounced effect of intracerebroventricular tapentadol was also observed after previous administration of NOS inhibitors in the Randall-Selitto test, but not in the tail-flick test. In conclusion, neuronal NOS, inducible NOS, and endothelial NOS influence the antinociceptive action of tapentadol at the spinal level and to a much lesser extent at the supraspinal level.

Involvement of NO in Antinociception of NSAIDS in Murine Formalin Hind Paw Assay

“…This finding is in agreement with a similar effect induced by 7nitroindazole in diazepam clonazepam,. chlordiazepoxide and tapentadol analgesia [18,24]. However, the effect of produced by 7nitroindazole is not consistent with the reported for modafinil and dexmedetomidine [19,25].…”

“…So, first the effectiveness of the nonselective inhibitor NOS, LNAME and the selective nNOS inhibitor, 7NI in increase the power of piroxicam, parecoxib, dexketoprofen and ketoprofen indicates that NO activity is involved in both phases of the hind paw formalin test. It is know, that after formalin administration, induces the release of substance P and glutamate and finally the release of NO that provokes central sensitization [19,24].Furthermore, studies with NOS inhibitors and cyclooxygenase inhibitor, suggest that NO stimulates the activity of COX. nNOS and LNAME has been involved in the spinal transmission of nociception in animal models of acute and chronic pain [7,11,13,14,26,27].…”

Neuronal Nitric Oxide Synthase

“…Neuronal NOS impact on the anti-nociceptive action of tapentadol at the spinal and supraspinal level [59].…”

The antipsychotic aripiprazole induces peripheral antinociceptive effects through PI3Kγ/NO/cGMP/KATP pathway activation

“…So, we believe that NO plays a pivotal role in controlling neuronal excitability to further produce analgesia. The literature shows that NO is responsible for important central (Bujalska‐Zadrożny et al, 2016; Galdino et al, 2015a) and peripheral (Costa et al, 2014; Ghorbanzadeh et al, 2019; Hervera et al, 2009; Ortiz et al, 2020; Romero et al, 2011b) antinociceptive effects. Therefore, the participation of this system in the aripiprazole mechanism of action was evaluated.…”