The activation of
mitogen-activated protein kinases (MAPKs) has been observed in synaptic plasticity processes of learning and memory in
morphine dependence. However, the role of extracellular signal-regulated
protein kinase 5 (ERK5), a member of MAPKs, has not been studied yet in
morphine dependence. To identify the function of ERK5 in the formation and development of
morphine physical
dependence, morphine withdrawal-like behavioral test and western blot technique were used in this research.
Morphine was subcutaneously injected by an intermittent and escalating procedure to induce physical dependence, which was measured by
withdrawal symptoms. In this study, spinal ERK5 signaling pathway was remarkably activated by chronic
morphine injection and
naloxone-precipitated withdrawal.
Intrathecal injection of
BIX02188, a novel specific inhibitor of
mitogen-activated protein kinases kinase 5 (MEK5), produced a dose- and time-dependent inhibition of the activation of spinal ERK5, without affecting activation of other MAPKs. Moreover, selective attenuation of spinal p-ERK5 expression by
BIX02188 could significantly relieve
morphine withdrawal symptom, accompanying with the decreased phosphorylation of
cAMP response-element binding protein (CREB) in the spinal cord. These findings suggested that activation of the ERK5 signaling pathway might contribute to
morphine physical dependence and its specific pharmacological inhibitor
BIX02188 could be a potential therapeutic choice for alleviation of
morphine withdrawal symptoms in the future.