Similarity and dissimilarity in antinociceptive effects of dipeptidyl-peptidase 4 inhibitors, Diprotin A and vildagliptin in rat inflammatory pain models following spinal administration

Mihaly Balogh, Bence Kalman Varga, David Arpad Karadi, Pal Riba, Zita Puskar, Mark Kozsurek, Mahmoud Al-Khrasani, Kornel Kiraly*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)


Dipeptidyl-peptidase 4 (DPP4) enzyme is involved in the degradation of many biologically active peptides including opioids. Its role in pain transmission is poorly elucidated. Recently we reported on the spinal antihyperalgesic effects of DPP4 inhibitors, Ile-Pro-Ile (Diprotin A) and vildagliptin in carrageenan-evoked acute inflammatory pain in rats. The present study investigated the effects of intrathecal (it.) diprotin A and vildagliptin in Complete Freund's Adjuvant- (CFA) and formalin induced pain in rats. The former assay can model the subchronic inflammatory pain condition and the later one reflects both acute tonic and inflammatory pain conditions. The involvement of opioid receptor (OR) subtypes, Y1-, and GLP1 receptors were also investigated.

In CFA pain model it. diprotin A or vildagliptin dose-dependently inhibits hyperalgesia in ipsilateral while has no effect in contralateral paws. The peak effect was achieved 30 min following drug administration which was used for further analysis. Both compounds showed naltrexone reversible antihyperalgesia. Co-administration of OR-subtype-selective antagonists with diprotin A and vildagliptin revealed involvement of and delta > mu opioid receptors, respectively. Co-administered Y1 but not GLP1 receptor antagonists reversed the antihyperalgesic action of both DPP4 inhibitors. In touch-hypersensitivity both compounds were ineffective. In formalin test only diprotin A showed and delta OR-mediated antinociception and only in the 2nd phase. This effect was Y1 or GLP-1 receptor antagonist insensitive. In conclusion, diprotin A and vildagliptin display antinociception of different mechanisms of action in subchronic inflammatory pain. Furthermore, the spinal pain relay points of inflammatory pain of acute or subchronic conditions were more effectively affected by diprotin A than vildagliptin which needs future elucidation.

Original languageEnglish
Pages (from-to)78-85
Number of pages8
JournalBrain Research Bulletin
Publication statusPublished - Apr-2019
Externally publishedYes


  • Dipeptidyl peptidase-4
  • Spinal administration
  • Inflammatory pain
  • Opioid
  • NPY
  • GLP-1
  • IV
  • CD26

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