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Pharmacological evaluation of the gabapentin salicylaldehyde derivative, gabapentsal, against tonic and phasic pain models, inflammation, and pyrexia

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Abstract

Gabapentinoids are effective drugs in most animal models of pain and inflammation with variable effects in humans. The current study evaluated the pharmacological activity of gabapentin (GBP) and its salicylaldehyde derivative (gabapentsal; [2-(1-(((2-hydroxybenzylidene) amino) methyl) cyclohexyl) acetic acid]; GPS) in well-established mouse models of nociceptive pain, inflammatory edema, and pyrexia at doses of 25–100 mg/kg. GPS allayed tonic visceral pain as reflected by acetic acid-induced nociception and it also diminished thermally induced nociception as a mimic of phasic thermal pain. Antagonism of GPS-induced antinociceptive activities by naloxone (NLX, 1.0 mg/kg, subcutaneously, s.c), beta-funaltrexamine (β-FNT, 5.0 mg/kg, s.c), naltrindole (NT, 1.0 mg/kg, s.c), and nor-binaltorphimine (NOR-BNI, 5.0 mg/kg, s.c), and pentylenetetrazole (PTZ-15 mg/kg, intraperitoneally, i.p) implicated an involvement of both opioidergic and GABAergic mechanisms. Tail immersion test was conducted in order to delineate the mechanistic insights of antinociceptive response. Inflammatory edema induced by carrageenan, histamine, or serotonin was also effectively reversed by GPS in a fashion analogous to aspirin (150 mg/kg, i.p), chlorpheniramine (1.0 mg/kg, i.p), and mianserin (1.0 mg/kg, i.p), respectively. Additionally, yeast-induced pyrexia was decreased by GPS in a comparable manner to acetaminophen (50 mg/kg, i.p). These observations suggest that GPS possesses ameliorative properties in tonic, phasic, and tail immersion tests of nociception via opioidergic and GABAergic mechanisms, curbs inflammatory edema, and is antipyretic in nature.

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Data availability

The authors declare that the data supporting the findings of this study are available within the article.

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Acknowledgements

We are thankful to Pakistan Council of Scientific and Industrial Research (PCSIR) laboratories for providing us the opioid antagonists beta-funaltrexamine, naltrindole, and nor-binaltorphimine for this study.

Code availability

Gabapentin (PubChem CID: 3446), aspirin (PubChem CID: 2244), chlorpheniramine (PubChem CID: 2725), mianserin (PubChem CID: 4184), acetaminophen (PubChem CID: 1983).

Funding

This study was financially supported by the Higher Education Commission of Pakistan (20-4422/NRPU/R and D/HEC 2014/307).

Author information

Authors and Affiliations

  1. Islam College of Pharmacy, Pasrur Road, Sialkot, Punjab, 51040, Pakistan

    Nisar Ahmad & Naseem Ullah

  2. Department of Pharmacy, Cecos University of IT and Emerging Sciences, Peshawar, Pakistan

    Fazal Subhan & Shehla Akbar

  3. Department of Pharmacy, Sarhad University of Science and Information Technology, Peshawar, Pakistan

    Nazar Ul Islam & Muhammad Shahid

  4. Department of Pharmacy, University of Peshawar, Peshawar, Pakistan

    Rahim Ullah

  5. Department of Pharmacy, Abasyn University, Peshawar, Pakistan

    Muhammad Khurram & Muhammad Usman Amin

  6. Department of Pharmacy, University of Swabi, Swabi, Pakistan

    Ihsan Ullah

  7. Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, UK

    Robert D. E. Sewell

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Contributions

FS, being the research supervisor, provided guidance to the research group. NA, FS, NI, and MS conceived the idea, in planning and conducting experiments throughout the study duration. NU, RU, MUA, and MK helped in providing the chemicals needed during the research work. SA and IU provided their input during the experiments. NA and MS performed the experiments and prepared the manuscript and RDES critically revised and helped in finalizing the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Nisar Ahmad.

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Ethics approval

All the experimental procedures employed in this study on live animals were conducted in compliance with the Animals’ Scientific Procedures Act 1986 (UK), the guidelines of Animal Research: Reporting In Vivo experiments (ARRIVE), and International Association for the Study of Pain (IASP). All the procedures were approved by the Animals Research Ethical Committee of the Department of Pharmacy, University of Peshawar (Reference No. 10/EC-15/Pharm) before commencement of the study.

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Ahmad, N., Subhan, F., Islam, N.U. et al. Pharmacological evaluation of the gabapentin salicylaldehyde derivative, gabapentsal, against tonic and phasic pain models, inflammation, and pyrexia. Naunyn-Schmiedeberg's Arch Pharmacol 394, 2033–2047 (2021). https://doi.org/10.1007/s00210-021-02118-x

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