Purinergic signaling: a potential therapeutic target for depression and chronic pain

Abstract

The comorbid mechanism of depression and chronic pain has been a research hotspot in recent years. Until now, the role of purinergic signals in the comorbid mechanism of depression and chronic pain has not been fully understood. This review mainly summarizes the research results published in PubMed during the past 5 years and concludes that purinergic signaling is a potential therapeutic target for comorbid depression and chronic pain, and the purinergic receptors A1, A2A, P2X3, P2X4, and P2X7and P2Y₆, P2Y₁, and P2Y₁₂ may be important factors. The main potential pathways are as follows: A1 receptor-related G protein-dependent activation of introverted K⁺ channels (GIRKs), A2A receptor-related effects on the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and MAPK/nuclear factor-κB (NF-κB) pathways, P2X3 receptor-related effects on dorsal root ganglia (DRG) excitability, P2X4 receptor-related effects on proinflammatory cytokines and inflammasome activation, P2X7 receptor-related effects on ion channels, the NLRP3 inflammasome and brain-derived neurotrophic factor (BDNF), and P2Y receptor-related effects on the phospholipase C (PLC)/inositol triphosphate (IP3)/Ca²⁺ signaling pathway. We hope that the conclusions of this review will provide key ideas for future research on the role of purinergic signaling in the comorbid mechanism of depression and chronic pain.

Introduction

As stated in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders, depression, as the second-most common cause of disability in the world [1], is also known as major depressive disorder (MDD). MDD is caused by various etiologies and is characterized as causing mood disorders that last for 2 weeks or longer, and depressive symptoms are the main clinical manifestations. As the world’s second-most common disease, the incidence of depression is increasing each year and seriously endangers the physical and mental health of the public. According to statistics from the World Health Organization (WHO), by the end of 2019, more than 350 million people in the world suffered from depression. According to data by Huang Y et al. [2], the lifetime prevalence rate of depression in China is 6.9%.. The International Association for the Study of Pain (IASP) defines chronic pain as “pain that exceeds the healing time of normal tissues (usually 3 months)” [3]. According to a recent survey, Chinese women (39.92%) and men (32.17%) have high prevalences of chronic pain [4]. Neuropathic pain manifests as spontaneous pain, hyperalgesia, allodynia, and paresthesias. Patients with chronic pain are prone to MDD, and patients with depression have more chronic pain symptoms than normal individuals [5]. Chronic pain with depression comorbid has been increased [6]. Since these two pathological conditions often coexist, understanding the potential common therapeutic targets for depression and chronic pain is important for formulating effective treatment strategies.

As early as 1970, Burnstock proposed the term “purinergic” [7]. The purinergic signal, that is, a nucleotide acting as an extracellular signaling molecule, was proposed in 1972 [8]. Medical terms such as purinergic receptor did not formally appear until 1978. Purinoceptors are divided into P1 and P2 receptors. P1 receptors include four types: adenosine (A)1, A2A, A2B, and A3. The P2 receptor group includes two categories: P2X and P2Y. Among them, there are 7 types of P2X receptors (P2X1–7) and 8 types of P2Y receptors (P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y_11-14). Adenosine triphosphate (ATP) binds to these receptors to induce cell-to-cell communication and inflammation propagation [9]. ATP binds to P2X receptors, which are ligand-gated ion channels (Na⁺, K⁺, and Ca²⁺) that regulate rapid responses; ATP and adenosine diphosphate (ADP) activate P2Y receptors, which are second messenger systems that act through the G protein, thereby regulating the release of various neurotransmitters and hormones [10].

The relationship between purinergic signals and depression was first proposed a century ago. Robin Ortiz proposed that purinergic signals, especially the regulation of P2 receptor subtypes, affected the level of upstream receptors and caused certain mood disorders through downstream behavioral effects [11]. Furthermore, purinergic signals, as important pharmacological targets for chronic pain treatment, could also change the qualities and quantities of downstream neurotransmitters through the mechanism similar to that of depression mentioned above [12]. A2A and P2X7R antagonists were reported to have antidepressant activity [9]. Therefore, we deduced that purinergic receptors could be used as targets for the treatment of chronic pain and depression comorbid diseases.

Glial cells and neurons are important participants in the transmission of purinergic signaling in depression and chronic pain. Among them, the reported receptors expressed by microglia are the P2X4 receptor (R), P2X7R [13], P2Y₁R, P2Y₂R, P2Y_2/4R, P2Y₆R, P2Y₁₂R, and P2Y₁₃R [14]. The receptors expressed by astrocytes are P2X1R [15], P2X3R [5], P2X1/5R [15], P2X4R, P2X7R [16], P2Y₁R[15], P2Y₄R [17], P2Y₁₁R [18], and P2Y₁₂R [19]. There is also a high level of P1R and P2R expression on neurons. Activating the above purine receptors on glial cells (microglia and astrocytes) and neurons can produce tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β [9], ATP, and other purines. Inflammatory factors can act as signaling molecules and bind to the corresponding receptors [20], causing depression [21] or chronic pain [22]. Previous studies have shown that purinergic signaling in glial cells and neurons is a key link in the molecular mechanism of depression and chronic pain [9]. Therefore, this review mainly explores the molecular mechanism of purinergic signaling as a potential therapeutic target for depression and chronic pain.

Adenosine receptors in depression and chronic pain comorbidity

Among the P1 receptors, A1R and A2AR are mainly involved in the mechanism of depression and chronic pain comorbid [9]. Adenosine, a natural by-product that accumulates during cellular respiration, is a neuromodulator and can bind to two G protein-coupled receptors with opposite functions in the central nervous system (CNS): Gi/o-coupled A1 receptors (A1Rs) and Gs-coupled A2A receptors (A2ARs). Activation of A1Rs and A2ARs inhibits or promotes the release of neurotransmitters associated with glial cells and neurons, respectively.

A1 receptor

Fritz BM et al. [22] used the in vitro whole-cell patch-clamp slice electrophysiological records of stinging neurons from the medial dorsal striatum (DMS) and lateral dorsal striatum (DLS) of C57BL/6 J mice and optogenetic methods to prove A1R-mediated spreading of the cortex and thalamic striatum was inhibited by regulating excitatory glutamate transmission. In addition, conditional A1R-KO mice lacking A1Rs at the input of the DMS and DLS were generated to directly determine the effect of these presynaptic A1Rs on the measured electrophysiological response, and it was concluded that the activation of presynaptic A1Rs produced significant synaptic inhibition of prolonged excitatory transmission, which may implicate their potential contribution to neuropsychiatric diseases [23]. Moreover, adenosine can bind to A1R, activate protein kinase A (PKA), inhibit calcium ion channels, activate K⁺ currents, and interact with phospholipase C (PLC), inositol triphosphate (IP3), and diacylglycerol (DAG), while extracellular signal-regulated kinase (ERK) and the β-arrestin pathway (β-arrestin) interact to alleviate chronic pain (Fig. 1) [24]. Based on this theory, MRS5474, a potent and selective A1AR agonist, has been put into use as an antidepressant without cardiovascular side effects [25]. The selective A1AR antagonist DPCPX [24] reversed the analgesic effect of local and systemic paracetamol or tramadol administration in the formalin test, which confirmed the contribution of glial cells and peripheral A1R to the analgesic effect (Table 1).

Fig. 1.

Potential mechanism by which A1 adenosine receptors are involved in the comorbidity of chronic pain and depression. ( ) on behalf of activation. ( ) and ( ) on behalf of inhibition

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

A2A receptor

A2AR in the striatum is activated by adenosine produced by extracellular nucleotidase-mediated degradation of ATP released by neurons and astrocytes [26]. Flajolet M pointed out that A2AR must be activated at the same time as the tyrosine kinase FGF receptor to cause strong activation of the mitogen-activated protein kinase (MAPK)/ERK pathway, which is associated with depression [27]. However, A2AR mainly plays a role in alleviating chronic pain by inhibiting the secretion of proinflammatory cytokines after the inflammatory response is activated [28]. Ko IG proposed that A2AR, as an important neuroregulator, may be involved in the activation of the MAPK/nuclear factor-kappa B (NF-κB) pathway: MAPK and NF-κB are stimulated by many factors, such as cytokine and cellular stress, and activation of MAPK/NF-κB (phosphorylation) can promote the expression of a variety of proinflammatory cytokines, thereby producing inflammation, which is one of the comorbid mechanisms of depression and pain [28]. Hamilton LJ et al. developed a new curcumin analog (cis-curcumin) as a ligand for A2AR that has the potential to treat chronic pain [29] (Table 1).

P2X receptors in depression and chronic pain comorbidity

P2X3 receptor

Chen Y et al. suggested that P2X3R was only expressed in small- and medium-diameter neurons in the dorsal root ganglia (DRG) [30]. However, in severe injury, an increase in ATP can increase the excitability of the DRG and promote the expression of P2X3R by activating TNF-α [31]. Neuronal P2X3R hyperexpression is induced by enhanced TNF-α signaling in the trigeminal ganglion (TG) [32]. The excitability of DRG neurons plays an important role in the neuroinflammatory pathway and participates in the production of depressive symptoms [33, 34]. P2X3 antagonists are also believed to control chronic pain from neuropathic pain sources, such as pain associated with overactive bladder and endometriosis [35]. P2X3R antagonists may be used to control chronic pain caused by inflammation or neuropathic pain. For example, the compound Gefapixant, which was named after Geoff (Gef = Geoff; pixant = P2X receptor antagonist), is expected to become the first P2X3 antagonist to be approved [36]. In addition, some articles suggest that as long-term depression was impaired in the P2X3 KO mice, it may play a role in the performance of the visible platform training (VPT). It is also possible that P2X3 receptor plays roles in anxiety and motivation, which could influence performance on the VPT [37]. However, in clinical studies, anxiety and depression are difficult to distinguish and mostly exist in combination. Systematic summary information is shown in Table 2.

Table 2.

The mechanism of depression and chronic pain comorbidity mediated by P2X receptors

P2X receptor subtype	Molecular mechanism	Method/experimental models	Type of disease	Treatment
P2X3R	P2X3 receptors play roles in anxiety and motivation, which could influence performance on the VPT, which may leads to depression [37]	P2X3 KO mice [37]	Depression	-
	Neuropathic pain or inflammation pathway [33, 34]	Quantitative real-time PCR, Western blotting, and double immunofluorescence/comorbid diabetic neuropathic pain and major depressive disorder rat model [33]	Chronic pain	Gefapixant [36]
P2X4R	Binding with ATP induces activation of microglia, releases proinflammatory cytokines, mainly IL-1β, and induces neuronal necrosis [40]	Morris water maze test/a natural aging rat model [40]	Depression and chronic pain	-
	Inflammasome NLRP3, pro-caspase-1 and the ASC increase the secretion of IL-1β and induce neuronal pyroptosis [41]	Sucrose preference test, forced swimming test, and open field test/chronic unpredictable mild stress-induced rats [41]	Depression and chronic pain	Hesperidin [41]
P2X7R	Activates the TLR4 signaling pathway and promotes the activation of NF-κB to mediate the production of IL-1β and IL-18 precursors, activate NLRP3, and thereby activate P2X7R [42]	Enzyme-linked immunosorbent assay, immunofluorescence staining, flow cytometry assay/chronic unpredictable mild stress-induced rats [42]	Depression and chronic pain	-
	The signal activated by P2X4R promotes the assembly of the NLRP3/CARD (ASC)/caspase-1 preprotein complex. Activated caspase-1 releases IL-1β and IL-18 to the extracellular space, thereby activating P2X7R [42]	Same as above	Depression and chronic pain	-
	Activating P2X7R, the outflow of K+ ions is compensated for by the influx of Ca2+ ions, leading to the loss of K+ in the cell or an increase in cytoplasmic Ca2+, thereby activating caspase-1, causing the proinflammatory cytokine IL-1β to activate, be released, trigger inflammation and induce other inflammatory mediators [46]	P2X7 receptor expressing gene knockout phenotypes [46]	Depression and chronic pain	-
	P2X7R activates the TRKB receptor in the ventral hippocampus and inhibits the level of BDNF-AKT-p70 S6 kinase [47]	Forced swim test/an animal model of depression based on selective breeding [47]	Depression	-
	CPSP increases P2X7R, ATP activates P2X7R, and Ca2+ promotes the release of glutamate and excessively enhances the thalamic γ-aminobutyric acid system, leading to rapid proinflammatory microglia maturation and the release of IL-1β [50]	Animal models for spinal cord injury [50]	Chronic pain	-

Abbreviations: P2X3R, P2X3 receptor; ATP, adenosine triphosphate; TNF, tumor necrosis factor; DRG, dorsal root ganglion; PCR, polymerase chain reaction; IL, interleukin; NLRP3, NOD-like receptor protein 3; ASC, apoptosis-related connexin dot-like protein including CARD; TLR4, Toll-like receptor 4; NF-κB, nuclear factor kappa B; TRKB, tropomyosin-related kinase B; BDNF, brain-derived neurotrophic factor; CPSP, central post stroke pain

P2X4 receptor

The activation of P2X4R on microglia is associated with depression [21], and neuroinflammation and inflammasomes, which are driven by the activation of P2X4R in microglia, are also closely associated with the development of chronic pain [38]. A study by Li L et al. [39] confirmed that P2X4R activation by ATP may induce microglial activation and proinflammatory cytokines, such as IL-1β, to induce hippocampal neuronal inflammatory changes [40]. Subsequent NOD-like receptor protein 3 (NLRP3) inflammasome activation also increases the secretion of IL-1β, but this pathway induces neuronal pyroptosis [41]. The NLRP3 inflammasome includes NLRP3, pro-caspase-1, and the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) (Fig. 2). Wang H et al. [42] concluded that IL-1β released by microglia via P2X4R also causes astrocyte activation but does not result in the synthesis or release of IL-1α and IL-1β. In summary, P2X4R may participate in the comorbid mechanism of depression and chronic pain by mediating hippocampal neuroinflammation (Table 2).

Fig. 2.

Potential mechanisms by which P2X4, P2X7, and P2Y₁₁ receptors are involved in the comorbidity of chronic pain and depression. ( ) on behalf of activation

P2X7 receptor

P2X7R is an important target for the comorbid mechanism and treatment of depression and chronic pain [43]. Chronic unpredictable stress (CUS) leads to increases in extracellular ATP, caspase-1, and IL-1β and causes the activation of P2X7R. P2X7Rs are mainly expressed in microglia and participate in the association between microglia and neurons. The rapid opening of potassium-selective channels leads to a sudden drop in intracellular potassium levels and the release of inflammatory cytokines, which mediate depression-like behavior [44]. However, with the accumulation of CUS, extracellular ATP, caspase-1, and IL-1β in the hippocampus were significantly increased, while this increase did not occur in P2X7-null mice [45]. In addition, the NLRP3 inflammasome can be activated by two signals. The first signal activates the Toll-like receptor 4 (TLR4) signaling pathway and promotes the activation of NF-κB to mediate IL-1β and IL-18 precursor production [38]. The second signal (described in the section on P2X4R) promotes the assembly of the NLRP3/ASC/caspase-1 complex, resulting in the release of IL-1β and IL-18 through activated caspase-1 to the extracellular space. Moreover, NLRP3 can activate P2X7R [41]. In the maintenance of neuropathic pain, the activation of P2X7 is also associated with the opening of ion channels and makes cells permeable to monovalent and divalent cations (Na⁺, K⁺, Ca²⁺). The outflow of K⁺ ions is compensated for by the influx of Ca²⁺ ions, which causes a loss of K⁺ ions in the cell induced by P2X7R or an increase in cytoplasmic Ca²⁺ ions to activate caspase-1. This activated caspase-1 further causes the rapid activation and release of the proinflammatory cytokine IL-1β from its inactive form. After that, the increased concentration of active IL-1β triggers inflammation and may also induce other inflammatory mediators, such as pro-caspase-1, nitric oxide synthase (NOS), cyclooxygenase-2 (COX-2), TNF-α, phospholipase D (PLD), phospholipase A2 (PLA2), NF-κB, and MAPK [46]. In short, P2X7R is related not only to depression but also to chronic pain (Fig. 2).

In addition, another mediator associated with P2X7R is brain-derived neurotrophic factor (BDNF). Ribeiro DE et al. [47] used a carrier or the P2X7R antagonist A-804598 (3, 10, or 30 mg/kg/day) to study BDNF signaling in the frontal cortex and ventral and dorsal hippocampus of rats for 1 or 7 days. The results showed that antagonizing P2X7R may block tropomyosin-related kinase B (TRKB) receptor activation and mediate an increase in BDNF-AKT-p70 S6 kinase levels in the ventral hippocampus, which produces related antidepressant effects. Central post stroke pain (CPSP) was used to examine continuous sensitization behavior [48]. The rat model showed that the expression of P2X7R in the surrounding areas of CPSP lesions was increased, and P2X7R was activated by ATP to elevate Ca²⁺. Ca²⁺ promotes the release of glutamate [49] and excessive enhancement of the thalamic γ-aminobutyric acid system [50], which leads to the rapid maturation of proinflammatory microglia and the release of IL-1β, resulting in chronic pain. Therefore, BDNF is also a potential target of P2X7R-mediated depression and chronic pain comorbidity via purinergic signaling. Systematic summary information is shown in Table 2.

P2Y receptors in depression and chronic pain comorbidity

P2Y₁R and P2Y₁₂R have been found in satellite glial cells (SGCs) of the trigeminal ganglia (TG) [48]. P2Y₁R, P2Y₂R, P2Y₄R, P2Y₅R, P2Y₁₃R, and P2Y₁₄R have been found in the SGCs of the DRG [51]. According to the G protein-coupled characteristics of P2YRs, these receptors can be divided into two categories: P2Y₁R, P2Y₂R, and P2Y₄R are coupled to Gq/G11 to activate the phospholipase C (PLC)/IP3/Ca²⁺ signaling pathway, while P2Y₁₂R, P2Y₁₃R, and P2Y₁₄R are coupled to Gi/Go and inhibit the synthesis of adenylate cyclase and cyclic adenosine monophosphate (cAMP) [52]. P2Y₁R is involved in the alleviation of depression [53]. Therefore, P2YRs are closely associated with depression [54]. In addition, P2Y₁₁R can be coupled to Gq/G11 and Gs to activate adenylate cyclase [52]. The activation of Gi/Go-coupled P2YRs can reduce behavioral hyperalgesia, while Gq/G11-coupled P2YRs can promote hyperalgesia [52]. Moreover, the activation of Gq/G11-coupled P2YRs is not necessarily excitatory. P2Y₁R activation reduces the expression and activity of P2X3R in DRG neurons [54, 55]. Therefore, we concluded that activated P2YRs regulate the activity of other channels or receptors through second messengers and participate in SGC and neuronal communication, which leads to chronic pain [56]. In addition, P2YRs in microglia play important roles in inflammation [57]. Activated P2Y₁₁R in microglia is coupled to Gs, leading to cAMP accumulation and PKA activation, which can alleviate depression (Fig. 2). P2Y₁₁R on microglia can mobilize intracellular calcium and activate Ca²⁺/calmodulin-dependent kinase (CaM kinase). P2Y₁₁R is coupled with Gs and Gq, leading to Ca²⁺mobilization in the inositol 1,4,5-triphosphate-sensitive reservoir [18]. In addition, the binding of ATP to P2Y₆R or P2Y₁₂R is associated with chronic pain mediated by spinal cord microglia. According to reports, P2Y₆R is a key receptor that activates the phagocytic function of microglia, and P2Y₁₂R is a key molecule that induces microglial chemotaxis and is associated with chronic pain [58]. G protein-coupled receptor kinase (GRK)2 can induce and regulate the intensity and duration of inflammation, leading to the transition from stress to depression and chronic pain [59]. In short, the role of P2YRs in the molecular pathways of depression and chronic pain cannot be ignored (Table 3).

Table 3.

The mechanism of depression and chronic pain comorbidity mediated by P2YRs

P2Y receptor subtype	Molecular mechanism	Method/experimental models	Type of disease	Treatment
P2Y1R, P2Y2R, P2Y4R, P2Y11R	Coupled with Gq/G11 to activate the PLC/IP3/Ca2+ signaling pathway [52]	P2Y1 knockout mice [52]	Depression and chronic pain	-
P2Y11R	Coupled with Gs, mobilizes Ca2+ in the inositol 1,4,5-trisphosphate-sensitive reservoir, and activates Ca2+/CaM kinase, leading to cAMP accumulation and PKA activation [18, 56]	Astrocyte-selective VNUT-knockout mice [18], symptomatic/end stage SOD1-G93A ALS mice [56]	Depression	-
P2Y12R, P2Y13R, and P2Y14R	Coupled with Gi/Go and inhibits the synthesis of adenylate cyclase and cAMP [52]	Immunohistochemical analysis, ratio metric calcium imaging [52]	Reduce chronic pain	-
P2Y6R, P2Y12R	Activates the phagocytic function of microglia, induces microglial chemotaxis, and is associated with chronic pain [57]	-	Chronic pain	-

Abbreviations: P2Y1R, P2Y1 receptor; PLC, phospholipase C; CaM kinase, calmodulin-dependent kinase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; VNUT, vesicular nucleotide transporter; ALS, amyotrophic lateral sclerosis

Conclusion and prospects

Based on purinergic signaling, this review summarizes the possible molecular mechanisms mediated by different purinergic receptors and explores the idea of purinergic signaling as a new potential drug target. A1R, A2AR, P2X3R, P2X4R, P2X7R, P2Y₆R, P2Y₁₁R, or P2Y₁₂R and purinergic signaling are potential common therapeutic targets in the comorbid mechanism of depression and chronic pain. Based on these findings, if future studies can truly verify that the purinergic signaling pathways mediated by these receptors exist in both depression and chronic pain, it will not be necessary to use traditional antidepressants and analgesics separately. Therefore, we infer that in the near future, the relevant targets described in this review will have common therapeutic effects on depression and chronic pain, such as inhibitors of the purinergic modulator xanthine oxidase (XO) [11], the P2X7R antagonists OxATP and BBG [16], the selective p38 MAPK inhibitor SB-681323, the p38 kinase inhibitor SCIO-469, and the NF-κB inhibitor parthenolide [60]. Although the combination of low-dose triptolide (T10), an HSP90 inhibitor, and fluoxetine (FLX), which act on P2Y₁₁ [18], is already a commonly used antidepressant, this combination may also be a more effective strategy for the treatment of depression and chronic pain comorbidity [61]. This mechanism may be closely associated with inhibiting the activation of microglia in the dorsal hippocampus, thereby reducing the inflammatory response in the hippocampus [62]. Wu-Tou decoction can have a synergistic therapeutic effect on pain and depression by inhibiting the activation of hippocampal microglia [63]. Purinergic receptors are involved in cellular neuroinflammatory responses, depression, and chronic pain in CNS [64, 65]. Purinergic signaling is related to brain circuits for pain and depression in CNS [66, 67]. This strategy requires further research to verify.

This review not only provides a basis and direction for how to better treat depression and chronic pain by changing the molecular mechanisms associated with purinergic signaling in the future but also facilitates a deeper understanding of purinergic receptors.

Yuting Zou

(drzytpeace@163.com; Tel: +86 13665715675), Undergraduate student. First Clinical Medical College of Nanchang University, No 461, BaYi Street, Donghu District, Nanchang 330000, Jiangxi, People’s Republic of China.

Funding

This work was supported by grants (Nos. 81861138042, 81870574, 81570735, and 31560276) from the National Natural Science Foundation of China.

Data availability

Not applicable.

Declarations

Ethical approval

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Informed consent

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Conflicts of interest

The authors declare no competing interests.