Altered processing in the central nervous system
Synaptic plasticity in the spinal cord dorsal horn
The changes in nociceptor functions following inflammation and axonal damage have profound consequences for pain processing in the central nervous system. Most information is available from animal studies on the changes in the spinal dorsal horn, the first station of central pain processing.
The secondary neurons of the nociceptive pathway are located in the superficial laminae of the dorsal horn. The transmission neurons in lamina I receive more or less specific input from nociceptors (nociception specific neurons), whereas larger multimodal projection neurons are found in lamina V. Both neuronal populations project to higher centres through the classical anterolateral spinothalamic tract and also through multisynaptic projections, relayed through brainstem nuclei.
It has been shown that low-frequency input from muscle nociceptors or even subthreshold synaptic potentials evoked by muscle nociceptors are sufficient to induce a long-lasting hyperexcitability in these neurons (Hoheisel et al. 2007). Important signs of central sensitization are increased neuronal activity to noxious stimuli, expansion of the receptive fields, and spread of excitation to other spinal segments (a phenomenon closely linked with expansion of the peripheral input). If central sensitization is established, innocuous tactile stimuli can become capable of exciting nociceptive projection neurons leading to ‘touch-evoked’ hyperalgesia (Tal et al. 1994).
Recent reviews provide comprehensive overviews of the plastic changes in nociceptive transmission neurons (Woolf and Salter 2000; Kuner 2010), a short synopsis of the most important mechanisms is given here.
Inflammation or nerve injury causes long-term potentiation in lamina I nociception specific neurons which express the neurokinin 1 receptor for substance P. This synaptic augmentation by a co-transmitter involves activation of T-type voltage gated calcium channels (Ikeda et al. 2003, 2006). Whereas substance P (together with CGRP and neurokinin A) acts as co-transmitter at spinal nociceptive synapses, the main transmitter is glutamate, acting at AMPA, NMDA, and metabotropic receptors. When the postsynaptic neurons are depolarized, a magnesium block of the NMDA-receptors is removed and a more profound depolarization takes place. This leads to short-term enhancement of synaptic transmission which may be the starting point of many longer lasting plastic changes. Whereas NMDA-R always permit Ca++ entry upon activation, AMPA-R influence the influx of Ca++ in a more subtle way, by expression and inclusion of subunits which cause greater Ca++ permeability (Burnashev et al. 1992). It has been shown that this mechanism is crucial for inflammation induced plasticity of spinal transmission (Hartmann et al. 2004; Luo et al. 2008).
A key effect of synaptic plasticity is the increase of intracellular Ca++ level which leads to the activation of several calcium-dependent kinases, e.g. CamKII alpha, cyclooxygenase-2 and NO-synthase. Their products, prostaglandin E2 and NO, have been shown to facilitate nociceptive transmission. Another important source of central sensitization is the mitogen-activated protein kinase (MAPK) system, ERK1 and 2 (Ji and Woolf 2001; Kawasaki et al 2004). ERK 1 and 2 can phosphorylate ion channels and thus induce a short term potentiation, but they play also a role in long term sensitization by acting as synapse-to-nucleus communicators changing gene transcription (Garry et al. 2003a, 2003b).
