A13 Chronic neuropathic pain (central sensitization)

Topic

A peripheral nerve injury is the starting point for chronic neuropathic pain: this injury generates ectopic activity in the damaged fibers—meaning it causes them to fire pain signals in the absence of an actual triggering stimulus. This ectopic activity arises because the damaged fibers overexpress voltage-gated sodium channels—the same channels involved in nerve fiber firing in other models. The more voltage-gated sodium channels the damaged fibers overexpress, the more ectopic activity they generate.

Among the damaged fibers, nociceptive C-fibers produce a specific effect on the spinal cord dorsal horn when repeatedly stimulated: each repeated stimulus from these fibers further potentiates the dorsal horn's neuronal response, causing successive responses to the same stimulus to become increasingly intense. The more frequently nociceptive C-fibers are stimulated, the greater this progressive potentiation of the dorsal horn's neuronal response becomes.

When this progressive potentiation of the dorsal horn's neuronal response is sustained over time, it solidifies into central sensitization of the dorsal horn. This occurs through a form of synaptic plasticity dependent on a specific type of glutamate receptor—the same type of plasticity involved in synaptic learning and excitotoxicity in other nervous system models.

This central sensitization of the dorsal horn is further compounded by a reduction in the descending inhibition that normally reaches the dorsal horn from supraspinal centers; the weaker this descending inhibition, the greater the dorsal horn's "net gain"—that is, the extent to which it amplifies each incoming signal. Both central sensitization and reduced descending inhibition drive the system in the same direction: they both increase the net gain of the dorsal horn.

This increase in dorsal horn net gain produces two characteristic clinical changes: on the one hand, it expands the peripheral receptive field of the dorsal horn—a phenomenon known as allodynia—meaning that previously innocuous stimuli, such as a light touch, begin to elicit pain; on the other hand, it lowers the dorsal horn pain threshold—known as hyperalgesia—meaning that mildly painful stimuli trigger pain that is far more intense than expected. Ultimately, it is this increase in dorsal horn net gain, stemming from the initial peripheral nerve injury, that explains why stimuli elicit a disproportionate pain response in chronic neuropathic pain.

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