The Actions and Mechanisms of P2X7R and p38 MAPK Activation in Mediating Bortezomib-Induced Neuropathic Pain

Abstract

The proteasome inhibitor bortezomib (BTZ) is a potent first-line anticancer drug for multiple myeloma; nonetheless, it induced peripheral neuropathy. It has been suggested that many cytokines may play a role in mediating neuropathic pain, but the underlying molecular mechanism is not fully understood. Recent studies have shown that neuropathic pain is closely related to the purinergic ligand-gated ion channel 7 receptor (P2X7R), one of the P2X receptors, which is richly expressed in glial cells. P2X7-p38 pathway is correlated with microglia- and satellite glial cell- (SGC-) mediated neuropathic pain. However, the association of P2X7R and p38MAPK in mediating BTZ-induced neuropathic pain remains unclear. In this study, the relationship between P2X7R activation and p38 phosphorylation in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) in the development and maintenance of BTZ-induced neuropathic pain was elucidated. The results showed that BTZ increased mechanical thresholds in rats, accompanied with upregulation of P2X7R expression and p38MAPK phosphorylation, indicating that P2X7R and p38MAPK are key molecules in the development and maintenance of BTZ-induced neuropathic pain. Inhibiting p38MAPK phosphorylation with SB203580 resulted in downregulation of P2X7R expression levels. Inhibition of P2X7R with Brilliant Blue G (BBG) reversed neuropathic pain might decrease through the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 via inhibiting p38MAPK phosphorylation. The P2X7R/p38MAPK signaling pathway in SGCs of DRG and microglia of SDH might be a potential pharmacological target behind this mechanism as an opportunity to relieve BTZ-induced neuropathic pain.

Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy

“…Mitogen-activated protein kinase (MAPK) signaling plays important roles in the development of BIPN. It has been shown that phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK are increased in DRG neurons [ 45 , 46 , 52 , 53 ]. In addition, pharmacological inhibition of these kinases was protective against bortezomib-induced sensory neuropathies [ 52 , 53 ].…”

“…Astrocytic JNK is highly phosphorylated and involved in bortezomib-induced neuropathic pain, and could be attenuated by intrathecal injection of an inhibitor of TNF-α or IL-1 signaling [ 60 ]. In addition to ERK and JNK, phosphorylation of p38 MAPK is reportedly increased by bortezomib [ 53 ].…”

“…A number of cytokines and chemokines in the spinal cord are affected by bortezomib. Specifically, expression of TNF-α and CCL21 were increased in dorsal horn neurons, while increased IL-1β and prokineticin-2 expression were observed in astrocytes [ 31 , 53 , 60 , 64 ]. In contrast, bortezomib decreased anti-inflammatory cytokines IL-4 and IL-10 in the spinal cord [ 31 , 33 ].…”

Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy

“…P2X7R downstream pathway inhibition could be able to revert neuropathic pain and the inhibition of p38 MAPK phosphorylation led to a downregulation of P2X7R expression level in BIPN-affected animals. These results indicated that blocking P2X7R-p38 signal with pharmacology therapy was beneficial to alleviate neuropathic pain resulting from BTZ treatment ( 213 ).…”

“…Interestingly, Guo and collaborators focused on the activation of microglia and SGCs (increase of Iba-1 and GFAP immunoreactive cells) after BTZ injection, indicating the crucial association between the purinergic ligand gated ion channel 7 receptor (P2X7R) and p38 MAPK pathway as a prerequisite for BIPN ( 213 ). P2X7R is richly expressed in glial cells.…”