Exchange proteins directly activated by cyclic adenosine monophosphate inhibitor reverses mechanical allodynia via the modification of astrocytes activity in the spinal cord

Gliosis and inflammation are pivotal in the development of acute and chronic pain. Here, we demonstrated a previously unidentified molecular mechanism in which the activation of exchange proteins directly activated by cyclic adenosine monophosphate (Epac)1 accelerated the activation of astrocytes in the spinal cord, thereby promoting chronic postsurgical pain (CPSP).

Spinal Epac1-mediated activation of astrocytes may facilitate CPSP. Inhibition of Epac1 may effectively prevent CPSP.

We established a rat model of CPSP induced by skin/muscle incision and retraction (SMIR). Pain behaviors were assessed using mechanical withdrawal threshold (MWT) at different times. The lumbosacral enlargement of the spinal cord was isolated to detect the expression of Epac1 and the activity of astrocytes. They were assessed using western blot and immunofluorescence staining.

SMIR induced persistent mechanical hyperalgesia after surgery. This hyperalgesia response was prolonged to more than 21 d after surgery. The time course of spinal Epac1 upregulation was correlated with SMIR-induced pain behaviors. Meanwhile, Epac1 immunoreactivity was colocalized primarily with astrocytes but not with microglial cells or neurons on 7 d after surgery. Intrathecal injection of Epac1 inhibitor CE3F4 significantly suppressed SMIR-induced mechanical allodynia and activation of astrocytes in the spinal cord. This analgesic effect of single-dose administration of CE3F4 lasted up to 6 h and wore off at 12 h after injection. Conclusions: Spinal Epac1-mediated activation of astrocytes may facilitate CPSP. Inhibition of Epac1 may effectively prevent CPSP.