CAV-1 Overexpression Exacerbates the Manifestation in EPAC-1-Induced Chronic Postsurgical Pain in Rats

Abstract

Purpose. Caveolae (CAV) are an invaginated microcapsule with the shape of Ω on the surface of the cell membrane. Caveolin-1 (CAV-1) is involved in neuropathic pain, and adenosine monophosphate (AMP)-exchange protein directly activated by cAMP1 (EPAC-1) is a potential therapeutic target for chronic pain. However, whether EPAC-1 promotes chronic postsurgical pain (CPSP) through CAV-1 has not been reported. Here, we aim to investigate the underlying mechanism of CAV in CPSP. Methods. All the rats were divided into 9 groups, including the Naive group, Sham group, skin/muscle incision and retraction (SMIR) group, SMIR + CAV-1 siRNA group, SMIR + control siRNA group, SMIR (7 days)+Saline group, SMIR (7 days)+CE3F4 group, 8-PCPT group, and Saline group. The CPSP rat model was established after SMIR. A mechanical withdrawal threshold (MWT) was recorded to evaluate the animal’s behavior. Western blotting and immunofluorescent were performed to detect the protein expression levels of EPAC-1 and P-CAV-1. Results. EPAC-1 and CAV-1 were both overexpressed after operation, particularly in astrocytes, microglia, and neurons of spinal marrow (all P < 0.05 ). Interestingly, CAV-1 siRNA can partly reverse the SMIR-induced hypersensitivity, but there was no effect on EPAC-1. Besides, EPAC-1 blockage partly reversed the SMIR-induced hypersensitivity and CAV-1 overexpression, and EPAC-1 activation promoted CAV-1 overexpression and hypersensitivity in normal rats (all P < 0.05 ). Conclusion. CAV-1 mediates the functional coupling of microglia, astrocytes, and neurons, and thus EPAC-1/CAV-1 plays an important role in CPSP exacerbation.

Role of EPAC1 in chronic pain

“…In a rat model of CPSP established by plantar incisions, EPAC has been shown to maintain the activation of nociceptive receptors that cause the transition from acute pain to chronic pain. Hua et al found that blocking EPAC1 can reverse CPSP induced by the Skin/Muscle Incision and Retraction (SMIR) model by inhibiting the overexpression of Cav-1 [ 84 ]. Cav-1 has been shown to regulate cellular endocytosis and vesicular transport, contributing to hippocampal synapses and neuroplasticity in mice [ 85 ].…”