Korean J Pain.  2024 Jan;37(1):26-33. 10.3344/kjp.23262.

Anti-inflammatory and antinociceptive effects of sitagliptin in animal models and possible mechanisms involved in the antinociceptive activity

• Hajhashemi V
• Sadeghi H
• Madab FK

• KMID: 2550129
• DOI: http://doi.org/10.3344/kjp.23262

Abstract

Background
Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity.
Methods
Male Swiss mice (25–30 g) and male Wistar rats (180–220 g) were used for formalin and carrageenan tests, respectively. In the formalin test, paw licking time and in the carrageenan test, paw thickness were considered as indexes of pain behavior and inflammation respectively. Three doses of sitagliptin (2.5, 5, and 10 mg/kg) were used in these tests. Also, several antagonists and enzyme inhibitors were used to evaluate the role of adrenergic, serotonergic, dopaminergic, and opioid receptors as well as the NO/cGMP/K ATP pathway in the antinociceptive effect of sitagliptin (5 mg/kg).
Results
Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly (P < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT ₂ ) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect.
Conclusions
NO/cGMP/K _ATP , 5HT₃ and D₂ pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test.

Keyword

Analgesics; Anti-Inflammatory Agents; Carrageenan; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Formaldehyde; Mice; Pain; Pain Measurement; Sitagliptin Phosphate

Figure

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  Fig. 1 The antinociceptive effect of three different doses of sitagliptin in formalin test. Data show mean ± standard error of the mean of 6 mice per group. ***P < 0.001 compared to control group (one way analysis of variance and Scheffe post hoc).

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  Fig. 2 Evaluation of the effect of adrenergic system on the antinociceptive effect of sitagliptin. Data show mean ± standard error of the mean of 6 mice per group. **P < 0.01 and ***P < 0.001 compared to control group (one way analysis of variance and Scheffe post hoc).

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  Fig. 3 The effect of cyproheptadine or ondansetron on the antinociceptive effect of sitagliptin. Data show mean ± standard error of the mean of 6 mice per group. ***P < 0.001 compared to control group. ##P < 0.01 compared to sitagliptin group (one way analysis of variance and Scheffe post hoc).

• 

  Fig. 4 The effect of naloxone on the antinociceptive effect of sitagliptin. Data show mean ± standard error of the mean of paw licking time of 6 mice per group. ***P < 0.001 compared to control group (one way analysis of variance and Scheffe post hoc).

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  Fig. 5 The effect of sulpiride on the antinociceptive effect of sitagliptin. Data show mean ± standard error of the mean of paw licking time of 6 mice per group. ***P < 0.001 compared to control group. ##P < 0.01 compared to sitagliptin group (one way analysis of variance and Scheffe post hoc).

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  Fig. 6 The effect of the drugs acting on NO/cGMP/KATP pathway on the antinociceptive effect of sitagliptin. All data are expressed as mean ± standard error of the mean of 6 mice per group. NO: nitric oxide, cGMP: cyclic guanosine monophosphate. *P < 0.05, **P < 0.01 and ***P < 0.001 compared to control group. #P < 0.05, ##P < 0.01 and ###P < 0.001 compared to sitagliptin group (one way analysis of variance and Scheffe post hoc).

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  Fig. 7 Anti-inflammatory effect of three different doses of sitagliptin in carrageenan test. *P < 0.05 and ***P < 0.001 refer to statistical significance from the control (one way analysis of variance and Scheffe post hoc).

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