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

•It. diprotin A produced μ opioid mediated analgesia in subchronic inflammatory pain.•It. diprotin A produced μ > δ opioid mediated analgesia in acute inflammatory pain.•It. vildagliptin showed δ opioid dominant analgesia in subchronic inflammatory pain.•Both compounds showed significant Y1 invol...

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Bibliographic Details
Published in:Brain research bulletin 2019-04, Vol.147, p.78-85
Main Authors: Balogh, Mihály, Varga, Bence Kálmán, Karádi, Dávid Árpád, Riba, Pál, Puskár, Zita, Kozsurek, Márk, Al-Khrasani, Mahmoud, Király, Kornél
Format: Article
Language:English
Subjects:
Analgesics - pharmacology
Analgesics, Opioid - pharmacology
Animals
Dipeptidyl peptidase-4
Dipeptidyl-Peptidase IV Inhibitors - metabolism
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
GLP-1
Hyperalgesia - metabolism
Inflammation - drug therapy
Inflammation - metabolism
Inflammatory pain
Male
Narcotic Antagonists - pharmacology
NPY
Oligopeptides - metabolism
Oligopeptides - pharmacology
Opioid
Pain - drug therapy
Pain - physiopathology
Pain Measurement
Rats
Rats, Wistar
Receptors, Opioid - metabolism
Receptors, Opioid, mu
Spinal administration
Vildagliptin - metabolism
Vildagliptin - pharmacology
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Summary:•It. diprotin A produced μ opioid mediated analgesia in subchronic inflammatory pain.•It. diprotin A produced μ > δ opioid mediated analgesia in acute inflammatory pain.•It. vildagliptin showed δ opioid dominant analgesia in subchronic inflammatory pain.•Both compounds showed significant Y1 involvement in subchronic inflammatory model. 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 μ and δ > μ 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 μ and δ 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.
ISSN:0361-9230
1873-2747
DOI:10.1016/j.brainresbull.2019.02.001