Glial cell type-specific changes in spinal dipeptidyl peptidase 4 expression and effects of its inhibitors in inflammatory and neuropatic pain

Abstract

Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states. In naïve animals, microglia and astrocytes expressed DPP4 protein with one and two orders of magnitude higher than neurons, respectively. DPP4 significantly increased in astrocytes during inflammation and in microglia in neuropathy. Intrathecal application of two DPP4 inhibitors tripeptide isoleucin-prolin-isoleucin (IPI) and the antidiabetic drug vildagliptin resulted in robust opioid-dependent antihyperalgesic effect during inflammation, and milder but significant opioid-independent antihyperalgesic action in the neuropathic model. The opioid-mediated antihyperalgesic effect of IPI was exclusively related to mu-opioid receptors, while vildagliptin affected mainly delta-receptor activity, although mu- and kappa-receptors were also involved. None of the inhibitors influenced allodynia. Our results suggest pathology and glia-type specific changes of DPP4 activity in the spinal cord, which contribute to the development and maintenance of hyperalgesia and interact with endogenous opioid systems.

Evaluation of the analgesic activity of single and multiple oral doses of teneligliptin (20 mg/day), using hot air analgesiometer in healthy human volunteers: a randomized, double blind, placebo controlled, cross over study

“…17 Kiraly et al reported that the expression of the DPP4 protein was increased by peripheral inflammation in astrocytes and also after neural injury (partial ligation of the sciatic nerve) in microglia suggesting that in pathological painful situations the role of DPP4 becomes more pronounced, therefore the effect of DPP4 inhibitors on nociception could also increase. 18 They reported that DPP4 inhibitors could activate the endogenous opioid system and cause an opioid-mediated anti-hyperalgesic effect in subacute inflammatory pain. Similarly, Balogh et al, in their study on rat inflammatory pain models reported that the anti-hyperalgesic effect of DPP4 inhibitors can be attributed to the activation of endogenous opioid system especially the delta opioid receptor.…”

Efficacy-Based Perspective to Overcome Reduced Opioid Analgesia of Advanced Painful Diabetic Neuropathy in Rats

“…After determination of the time of peak effect further analysis was made at that time point. An animal was considered neuropathic, when the PPT value was at least decreased by 20% compared to weight match animals as described previously (Király et al, 2018).…”

Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders?

“…MERS-CoV has the potential ability to enter microglia, astrocytes, and neurons, considering that all these cell types express DPP4 ( Király et al., 2018 ; Elkjaer et al., 2019 ). Among these CNS cells, glial fibrillary acidic protein-positive (GFAP+) astrocytes seem to show the largest DPP4 basal expression, and inflammation significantly increased the expression of the viral receptor ( Király et al., 2018 ), thus allowing a feed-forward loop that increases MERS-CoV access to glial cells. Moreover, DPP4 was also found in brain microvasculature ( Kenny and Bourne, 1991 ; Zeng et al., 2019 ) turning endothelial cells into another MERS-CoV potential target.…”