Microgliosis occurs after morphine and peripheral nerve injury alone, but the behavioral and molecular impact in tandem is unknown. We hypothesized that sciatic chronic constriction injury (CCI)-allodynia would be enhanced by subsequent repeated morphine in rats, involving TLR4, P2X7 receptor (P2X7R) and caspase-1, facilitating release of interleukin (IL)-1β. Beginning 10days after CCI, morphine (5mg/kg b.i.d.) or saline was administered for 5days. Compared to vehicle, morphine significantly prolonged the duration of CCI-induced allodynia (n=6/group; p<0.05). Morphine also significantly elevated TLR4 mRNA, P2X7R, NFkappaB, NLRP3 and caspase-1 protein levels (p<0.05) in the ipsilateral lumbar dorsal quadrant (iLDQ), 5weeks after dosing conclusion. Supporting a causal role for NLRP3 inflammasome activation in morphine-prolonged CCI-allodynia, continuous intrathecal infusion of inhibitors of TLR4 ([+]-naloxone; 60 micrograms/h), P2X7R (Brilliant Blue G; 30ng/h), or caspase-1 (ac-YVAD-cmk; 1μg/h) prevented prolonged allodynia when administered concomitantly with morphine, and abolished established morphine-prolonged CCI-allodynia when administered 5weeks after morphine dosing (n=6/group; p<0.05). A single intrathecal IL-1 receptor antagonist dose (100 micrograms) also attenuated morphine-prolonged CCI-allodynia (n=6/group; p<0.05). In keeping with known pro-nociceptive roles for IL-1β, phosphorylation of the NR1 NMDA subunit was elevated, while GRK2 levels and GLT-1 mRNA were decreased in iLDQ 5weeks after dosing conclusion (p<0.05). These data suggest that morphine and the products of nerve injury interact, resulting in prolonged neuropathic pain via sustained inflammasome signaling.