Background.Bortezomib(BTZ)is a regularly used first-line chemotherapeutic drug for the therapy of refractory multiple myeloma and hematological neoplasms.However,the underlying mechanism that the application of BTZ leads to painful peripheral neuropathy still remains unclear.Since BTZ are unlikely to be without side effects for the majority of multiple myeloma patients,its imperative for us to find out an investigational agent that can overcome BTZ-induced neuropathic pain.Methods.MaleSprague Dawley rats(220 –250g)were used in this study.Bortezomib was intraperitoneally injected at 0.4 mg/kg once per day for five consecutive days.Intrathecal injection of MCC950 or S3I-201was performed.Recombinant AAV encoding NLRP3(pAAV-CMV-Nlrp3-3FLAG)was intrathecal injected into the subarachnoid space of L4-L6 spinal cord of na(i)ve rats.Control rats were injected withAAV encoding negative control(pAAV-CMV-MCS-3FLAG).The 50%withdrawal threshold was assessed using von Frey hairs to evaluate the pain behavior following BTZ treatment.Real-time quantitative PCR,western blot and immunohistochemistry were performed to explore the molecular mechanisms.Results.The co-location ofnucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)andionized calcium binding adaptor molecule 1(Iba1)and NeuN protein expression supported that microglia and neuron in spinal dorsal horn was the primary contributor for BTZ-induced NLRP3 inflammasome activation in rats.Moreover,intrathecal injection of NLRP3 activation inhibitor MCC950,significantly prevented the mechanical allodyniainduced by BTZ treatment.Following intrathecal injection of recombinant adeno-associated virus vectorencoding NLRP3(pAAV-CMV-Nlrp3-3FLAG)under the normal Nlrp3 promoter in rats,the expression of NLRP3 was markedly upregulated in spinal cord and the rats showed obvious mechanical allodynia,compared to the rats with injection of recombinant adeno-associated virus vectorencodingnegativecontrol(pAAV-CMV-MCS-3FLAG).In addition,we also found that systemic administration of BTZ for consecutive 5 days significantly induced the activation of signal transducer and activator of transcription 3(STAT3)in spinal cord of rats.Western blot showed that the ratio of p-STAT3/STAT3 increased after administration of BTZ Inhibition of STAT3 activity by S3I-201 reducedthe upregulation of NLRP3 mRNA and protein levels in spinal cord andprevented mechanical allodynia induced by BTZ treatment.Immunohistochemistry results also revealed that the expression of p-STAT3 were colocalized with NLRP3-positive cells in spinal cord.Conclusions.These findings provide in vivo evidence that upregulation of microglial and neuronal NLRP3inflammasome in spinal dorsal hornvia activating STAT3 is a mediator of central sensitization during BTZ-induced neuropathic pain,and suggest a new therapeutic target for the prevention and treatment of chemotherapy-induced neuropathic pain.