Spinal heat shock protein 27 participates in PDGFRβ‐mediated morphine tolerance through PI3K/Akt and p38 MAPK signalling pathways

Abstract

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 PDGFRβ in morphine tolerance. Here, we have investigated the role of spinal heat shock protein 27 (HSP27) in morphine tolerance and its relationship with PDGFRβ activation. Experimental Approach: Rats were treated with morphine for 9 days, and its antinociceptive 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, PDGFRβ, 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. PDGFRβ antagonism inhibited HSP27 activation and attenuated and reversed morphine tolerance. PDGFRβ induction increased HSP27 expression and activation and partly decreased morphine analgesia. PDGFRβ 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 PDGFRβ-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.

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“…It is known that HSPs are a class of transcription‐regulated proteins, associated with bone metabolism and can be stimulated by chemical stress and heat stress. [ 61 ] To further study the stimulation mechanism of the osteogenic differentiation, the genes expressions of heat shock proteins (HSP27 and HSP90) and Smads (Smad1 and Smad5) were further measured on T‐S2P1 with or without NIR irradiation, and Ti was used as a control ( Figure a). Compared with Ti, HSPs and Smads are increased in expression on T‐S2P1, especially on the irradiated group.…”

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