Central Sensitization

The pain pathway can be modulated from within the central nervous system as well by a phenomenon called central sensitization. The dorsal horn itself can modulate its own excitability. Repetitive activation of nociceptive input can alter the ascending pain pathway. Persistent C fiber activation of lamina I and lamina V occurs with tissue injury and inflammation. Lamina V’s WDR neurons enhance the dorsal horn’s response to further nociceptive input. WDR neurons are unique in that the intensity of the response increases with increased frequency of stimulation even though the strength of the stimulation stays constant. This can result in over-excitation of the nociceptive signal. In addition, the receptive field of activated neurons enlarges so that dermatomal areas not previously activated are now responsive. This effect has been called “wind-up.”³⁵ Chronic neuropathic pain has been linked to WDR neurons. WDR neurons are also activated by sympathetic pathways and can be temporarily blocked by sympathetic blockade.³⁶

Bliss and Lomo described long-term potentiation (LTP) in the hippocampus where brief high- frequency coincident input resulted in a persistent increase in synaptic efficacy.³⁷ This phenomenon was later recorded in the spinal cord as part of the central sensitization process.³⁸³⁹ This synaptic plasticity shares striking similarities with the process of memory.⁴⁰ With LTP, the facilitation manifested after the stimulus—that is to say that for some time, only a low level of nociception was required to sustain the stimulation. Nociceptive inputs that are normally sub-threshold create excitation. This is distinct from wind-up where the facilitation occurs with continued stable but high- frequency stimulation.⁴¹ Long-term depression (LTD) is an opponent process to LTR LTD occurs in response to weak or low-frequency stimulation ⁴

The N-methyl-D-aspartate (NMDA) receptor has been well-implicated in the development of wind-up. The NMDA receptor is an ionotropic glutamate receptor (glutamate receptor and an ion channel). At normal resting potential, the ionophore channel is blocked by Mg²⁺. With the Mg²⁺ block in place, glutamate will not be able to open the channel. However, with repetitive stimulation by AMPA and SP, the Mg²⁺ block is removed. If secondary glycine or D-serine sites are also occupied, activation of the NMDA receptor by glutamate can then allow entry of Ca²⁺ and Na⁺ into the cell, and K⁺ out of the cell. So not only is the cell depolarized, but there are increased intracellular stores of Ca²⁺ as well. Wind-up has been prevented by the administration of NMDA receptor antagonists.⁴²-⁴⁴

The increased intracellular concentration of Ca²⁺ promotes the externalization of phospholipases to the cell membrane which then cleave arachidonic acid and is acted upon by cyclooxygenase to produce prostanoids. Prostaglandins act pre- and post-synaptically. The pre-synaptic effect enhances the opening of voltage gated calcium channels. Post-synaptically, glycine receptors are inhibited. Glycine typically acts as an inhibitory neurotransmitter on the second-order neuron.

Increased intracellular concentration of Ca²⁺ also results in increased levels of nitric oxide synthase which in the presence of arginine allows for the release of nitric oxide. Nitric oxide impacts the pre-synaptic neuron to enhance the release of excitatory glutamate neurotransmitter.

Increased intracellular concentration of Ca²⁺ also activated multiple protein kinases. Protein kinases result in multiple changes. Amino acid sites on NMDA and AMPA receptors are phos- phorylated, lowering the activation threshold. Phospholipase-A₂ is phosphorylated which activates transcription factors such as nuclear factor-КВ, which increased the synthesis of inflammatory proteins, channels, receptors, and transcription factors.²⁸

With nerve injury, there is an upregulation several types of sodium channels (especially the oc₂5 subunit) and downregulation of potassium channels. This is noted at the superficial dorsal horn in the substantia gelatinosa and in the DRG. Hence, the anti-nociceptive actions of gabapentin or intrathecal ziconotide.

Central sensitization can also occur from non-neuronal cells resident in the central nervous system. In addition to neurons, the central nervous system contains supportive glia cells such as astrocytes, microglia, and oligodendrocytes. Astrocytes envelop the synapse and secrete and absorb neurotransmitters. Microglia are essentially resident macrophages in the CNS. These glia cells are considered to be an important contributor to the synapse—so much so that the synapse has been referred to as tripartite. Microglia typically exist in a resting state. With appropriate stimulation, glia cells can shift into an activated, reactive, pro-inflammatory response profile—creating neuronal excitability and removing the “brake” on excitability. Sensory afferents can increase glutamate release. Upregulation in the number and conductance of calcium-permeable AMPA and NMDA receptors is noted. Inhibitory GABA receptors are down regulated. Glial glutamate transporters are downregulated. Astrocytes typically regulate extracellular glutamate concentration by utilizing an active uptake system. However, during certain situations, these stores can be dumped out, resulting in significant increases in glutamate concentration. Astrocytes may become “activated” after microglial activation and communicate on a broader network basis via gap junctions which may result in the reversal of glutamate transporters. Once microglia become activated, they do not return to a normal resting state but remain “primed.”

Neurotransmitters such as glutamate, SP, and ATP can be taken up by glia cells to activate them. Second-order neurons can secrete fractalkine which activate the microglia. Circulating cytokines may activate glia cells. Astrocytes may themselves communicate with the microglia via S-100 protein or cytokines. Peripheral nerve injury can elicit endogenous danger signals or “alarmins” which activate the glia by binding to innate immune pattern recognition receptors such as toll-like receptors. Examples include degradation products of the extracellular matrix, components of circulating blood not normally having access to the extracellular space—such as fibrinogen—or substances released from damaged or dying cells (nuclear protein HMBG1, HSP, or DNA). The activation of toll-like receptors (TLRs) activates glia cells. TLR4 agonists have been shown in DRG cells to increase intracellular Ca²⁺ and lead to the release of neurotransmitters.⁴⁵-⁴⁶ In the presence of bone cancer, there is significant activation of glia.