Spinal Heat Shock Protein 27 Participates In Pdgfr Beta-Mediated Morphine Tolerance Through Pi3k/Akt And P38 Mapk Signalling Pathways

Background and Purpose: The development of antinociceptive morphine tolerance is a clinically intractable problem. Earlier work has demonstrated the pivotal roles of PDGF and its receptor PDGFR beta in morphine tolerance. Here, we have investigated the role of spinal heat shock protein 27 (HSP27) in morphine tolerance and its relationship with PDGFR beta activation.Experimental Approach: Rats were treated with morphine for 9 days, and its anti-nociceptive effect against thermal pain was evaluated by a tail-flick latency test. Western blot, real-time PCR, immunofluorescent staining, and various antagonists, agonists, and siRNA lentiviral vectors elucidated the roles of HSP27, PDGFR beta, and related signalling pathways in morphine tolerance. Key Results Chronic morphine administration increased expression and phosphorylation of HSP27 in the spinal cord. Down-regulating HSP27 attenuated the development of morphine tolerance. PDGFR beta antagonism inhibited HSP27 activation and attenuated and reversed morphine tolerance. PDGFR beta induction increased HSP27 expression and activation and partly decreased morphine analgesia. PDGFR beta inhibition reduced Akt and p38 MAPK activity in morphine tolerance. PI3K and p38 inhibitors reversed morphine tolerance and suppressed morphine-induced HSP27 phosphorylation.Conclusion and Implications: This study demonstrated for the first time that spinal HSP27 participates in PDGFR beta-mediated morphine tolerance via the PI3K/Akt and p38 MAPK signalling pathways. These findings suggest a potential clinical strategy for prolonging the antinociceptive effects of opioids during long-term pain control.