In this study, we found a significantly increased expression of P2X7R mRNA and protein in lymphocytes and monocytes as well as higher IL-1β serum levels in patients suffering from NeP, but not in those with nociceptive CLBP. These results might point to an important role of P2X7R and IL-1β in the pathogenesis and maintenance of NeP.
Chronic pain is a global health problem, affecting up to 60 % of the population [
26]. Over the last years, significant effort has been made to investigate endogenous pain-modulating factors [
27]. In various animal models of nociceptive, inflammatory, and neuropathic pain, the endogenous receptor P2X7 was the focus of interest [
2‐
5]. Recent data indicate that nociceptive information from the periphery to the CNS is transmitted through various ion channels and receptor pathways [
28,
29]. The ATP-sensitive P2X7R, which is particularly localized on immune and microglial cells, is part of this reporter system [
29]. In response to inflammation or cellular damage, ATP activates P2X7R, which represents an important step in the transmission of sensory information to the central nervous system [
4,
30]. Recent studies suggest that P2X7R is involved in the pathogenesis of neurological disorders such as epilepsy, stroke, neuralgia, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease [
31]. Moreover, the P2X7R is associated with mood disorders like major depression or anxiety [
31,
32]. Upon activation, P2X7R triggers a series of physiological events that culminate in the posttranscriptional processing and release of IL-1β from monocytes [
10]. IL-1β is a pro-inflammatory and pro-nociceptive cytokine which was shown to be a key mediator in chronic pain [
33]. In addition, there is increasing evidence that enhanced release of IL-1β after P2X7R activation antagonizes morphine analgesia and accounts for the development of morphine tolerance, which may partly explain the insufficient effect of opioids in a considerable number of NeP patients [
34]. IL-1β induces the transcription of cyclo-oxygenase 2 (COX-2) and nitric oxide synthase (iNOS), which play a central role in the generation and maintenance of pain [
35,
36]. Within clinical settings, the efficacy of agents to treat neuropathic pain is variable. While COX-2 inhibitors are particularly effective against the inflammatory component of neuropathic pain, their effect on the intensity of pain is generally not satisfactory [
37]. Contrary, antiepileptic drugs and antidepressants are useful to modulate the intensity of pain, but rather inefficient to treat the inflammatory component [
38]. P2X7R and IL-1β are known to modulate inflammation and nociception, which recently led to the discovery of pharmacological agents selectively blocking P2X7R [
30]. Genetic modulation or pharmacological blockade of P2X7R induces a regression of symptoms in animal models of neurological disorders and reduces the intensity of inflammatory and neuropathic pain in mice [
4,
39,
40].
These findings are consistent with our results demonstrating an increased expression of lymphocyte and monocyte P2X7R and IL-1β in patients suffering from NeP. It is not surprising, that only slight elevations of P2X7R protein, P2RX7 mRNA expression and of IL-1β levels were found in patients with CLBP, as CLBP is usually not associated with significant immune activation. These findings might point to a minor role of the P2X7R/IL-1β interplay in the pathophysiology of CLBP. This assumption is supported by recent research, showing a communication link between the immune system and the CNS [
1,
15]. Lesion of a peripheral nerve leads to both a transition of microglia to the side of damage and an infiltration of immune cells in the vicinity of the synapse between primary afferent fibers and nociceptive neurons in the dorsal horn of the spinal cord [
41,
42]. These activated immune cells release many pro-inflammatory mediators, such as IL-1β which cross the blood-brain barrier [
15] and modulate pain intensity [
40,
43]. A crucial regulator of IL-1β release is P2X7R [
10]. Peripheral knock-down of P2X7R in mice leads to a significant decrease of IL-1β release and reduction of pain intensity [
40].
Since elevated P2X7R expression has also been associated with mood disorders such as depression and anxiety, we tested the CES-D depression scores and KAB values as potentially confounding variables. Healthy volunteers had significantly lower depression and stress scores than both patient subgroups, but no differences were found between patients suffering from CLBP or NeP. In order to exclude further factors being responsible for the different expression of P2X7R/IL-1β in pain syndromes, we performed confounder-analyses. Although age differed between patients and healthy volunteers, a potential confounding effect could be excluded. Furthermore, we found that gender did not correlate with the expression of P2X7R or IL-1β either. Regarding subgroups of NeP, no differences with respect to the P2X7R expression were found between patients suffering from peripheral polyneuropathy/mononeuropathy, postherpetic neuralgia or orofacial pain. One limitation of our study is that the analysis of P2X7R protein and mRNA expression was performed on lymphocytes, whereas IL-1β levels were determined in the peripheral blood. Since P2X7R is also expressed on the surface of other immune cells such as macrophages, which are also a major source of IL-1β production, further studies are needed to clearly define the source of elevated IL1β levels. Furthermore, it would be interesting to take the monocytes followed by LPS priming and ATP challenge to demonstrate different IL-1β release between groups.