Abstract
Chronic pain, resulting from injury, arthritis, and cancer, is often accompanied by inflammation. High concentrations of protons found in inflamed tissues results in tissue acidosis, a major cause of pain and hyperalgesia. Acidosis signals may mediate a transition from acute to chronic hyperalgesia (hyperalgesic priming) via proton-sensing G-protein-coupled receptors (GPCRs). The expression of T-cell death-associated gene 8 (TDAG8), a proton-sensing GPCR, is increased during inflammatory hyperalgesia. Attenuating TDAG8 expression in the spinal cord inhibits bone cancer pain, but whether TDAG8 is involved in inflammatory hyperalgesia or hyperalgesic priming remains unclear. In this study, we used TDAG8-knockout or -knockdown to explore the role of TDAG8 in pain. Suppressed TDAG8 expression delayed the onset of inflammatory hyperalgesia and shortened hyperalgesic time in mice. In a dual acid-injection model (acid [pH 5.0] injected twice, 5 days apart), shRNA inhibition of TDAG8 shortened the duration of the second hyperalgesia. Similar results were found in TDAG8-deficient mice. The dual administration of TDAG8 agonist also confirmed that TDAG8 is involved in hyperalgsic priming. Accordingly, TDAG8 may mediate acidosis signals to initiate inflammatory hyperalgesia and establish hyperalgesic priming.
Highlights
In this study, we used TDAG8 shRNA to knock down TDAG8 gene expression for determining whether TDAG8 is involved in the transition from acute to chronic pain
To understand whether TDAG8 is involved in inflammatory hyperalgesia, we first subcloned TDAG8-shRNA plasmids into pLKO.1-Cherry vector (Table 1) and tested their knockdown efficiency on co-transfection with TDAG8-EGF in HEK293T cells. shTDAG8 expression reduced the fluorescence intensity of TDAG8-EGFP in co-transfected cells (Fig. 1A)
We examined whether TDAG8 is involved in mechanical hyperalgesia induced by inflammation. shTDAG8-B1 was delivered into mice before carrageenan injection 7 days later
Summary
We used TDAG8 shRNA to knock down TDAG8 gene expression for determining whether TDAG8 is involved in the transition from acute to chronic pain. Knocked-down TDAG8 expression delayed the initiation of mechanical hyperalgesia in mice with acid, carrageenan, or CFA injection. Inhibition of TDAG8 expression reduced cAMP accumulation and Ca2+ signals in DRG neurons. With dual acid injection, knocked-down TDAG8 expression shortened the hyperalgesia induced by the second acid injection. TDAG8 activation may regulate cAMP signalling to participate in initiating inflammatory hyperalgesia and establishing hyperalgesic priming
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