Table 1.

The mechanism of depression and chronic pain comorbidity mediated by P1 receptors

P1 receptor subtype	Molecular mechanism	Method/experimental models	Type of disease	Treatment
A1R	Coupled with Gi/o; activates presynaptic A1R to produce synaptic inhibition and prolong the duration of excitatory transmission [23]	In vitro whole-cell patch-clamp slice electrophysiological records, optogenetic methods/C57BL/6 J mice, A1R-KO mice [23]	Depression	MRS5474 [25]
	Adenosine can bind to A1R, activate PKA, inhibit calcium channels, activate K+ currents, and interact with PLC, IP3, and diacylglycerol [24]	Immunohistochemistries/a rat model of unilateral lingual nerve crush [24]	Chronic pain	DPCPX [25]
	ERK and β-arrestin pathway [24]	-	Chronic pain	DPCPX [25]
A2AR	ATP and the tyrosine kinase FGF receptor simultaneously activate A2AR and the MAPK/ERK pathway [27]	The yeast two-hybrid method/E. coli[27]	Depression	-
	Activates the secretion of proinflammatory cytokines [29]	Photochemical method/a novel isomer of curcumin (cis–trans curcumin or CTCUR) [29]	Chronic pain	Cis-curcumin [29]
	Phosphorylation of MAPK/NF-κB pathway factors to promote the expression of a variety of proinflammatory cytokines [28]	Cyclophosphamide-induced interstitial cystitis rats [28]	Depression and chronic pain	-

Abbreviations: A1R, A1 receptor; PKA, protein kinase A; PLC, phospholipase C; IP3, inositol triphosphate; ERK, extracellular signal-regulated kinase; ATP, adenosine triphosphate; A2AR, A2A receptor; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB