Figure 5

A schematic illustration of spinal glial activation in monoarthritic pain. Joint inflammation may increase the release of nociceptive transmitters and modulators (such as EAAs, SP, ATP and CX3CL1) in the spinal dorsal horn from the primary afferent terminals ipsilateral to the inflammed joint[39]. These events can initiate early focal microglial activation in ipsilateral spinal cord (within 4 hrs after MA). Activated microglia release several proinflammatory cytokines and chemokines that may spread to contralateral spinal cord, leading to the contralateral spinal microglial and astrocytic activation[3]. Once the glia are activated, they release several glial products including proinflammatory cytokines, tumor necrosis factor-α, and inflammatory mediators. This leads to an exaggerated release of neurotransmitters from presynaptic neurons, sensitization of the post-synaptic membrane, activation of neighboring astrocytes, and enhancement of the microglial propagation of neuromediators[5]. Such positive feedback loops sustain the perseverant release of pain mediators, facilitating the development of neuronal hypersensitivity, leading to exaggerated pain (such as thermal hyperalgesia)[13]. Gabapentin might diminish the release of “pain” neurotransmitters/neuromodulators (such as CX3CL1) and activation of microglia in the spinal cord by modulating VGCC α2/δ-1 subunits, leading to a reduction in thermal hyperalgesia.