In experiments, central sensitization has been observed during peripheral inflammation and also in models of neuropathic pain. Research in humans suggests that central sensitization may indeed be present in a number of different pain states, such as inflammation, osteo-
arthritis, fibromyalgia, migraine attacks, and others.
Concerning molecular mechanisms of central sensitiza-tion, several points must be made. First, an important basis for central sensitization is the potential of nocicep-tive spinal cord neurons to undergo neuroplastic changes. The latter can, for example, be shown with defined protocols of electrical nerve stimulation. Electrical stimulation of C-fibers can induce wind-up of the responses to electrical nerve stimulation96 (a short-lived increase of responsiveness, however, not outlasting the stimulation protocol) or a long-term potentiation97 (a persistent increase of synaptic responses to electrical stimulation outlasting the conditioning stimulus). Second, while for central sensitization under inflammatory conditions mainly an increase of excitatory mechanism is being discussed, in the case of neuropathic pain loss of inhibition (e.g. by apoptosis of inhibitory interneurons) has been proposed as an important mechanism.98 Third, again in studies on neuropathic pain, an involvement of both neurons and glial cells has been shown.99 These data suggest that different mechanisms may contribute to central sensitization in different pain states. Ongoing research has to dissect out which mechanisms are particularly important for different pain states.
In the case of inflammation in joint and muscle, the contribution of transmitters and receptors to central sensitization has mainly been studied. Once inflammation develops in the joint, the intraspinal release of gluta-mate100 (the main transmitter of nociceptive afferents) and neuropeptides (cotransmitters in primary afferents and interneurons) is enhanced. While only noxious compression of the normal joint enhances the intraspinal release of substance P, neurokinin A, and CGRP above baseline, these excitatory peptides are intraspinally released even by innocuous compression when the joint is inflamed.101,102103 Intraspinal release of substance P is also evoked by palpation of bone with cancer.14 In addition, the intraspinal milieu is altered by (enhanced) release of further mediators. For example, prostaglandin E2 is tonically released above baseline within the dorsal and ventral horn.104 This is likely to result from an up-regulation of spinal COX-2, that is already present at three hours after induction of knee joint inflammation.104 Thus, as a presynaptic mechanism, a cocktail of transmitters and/or modulators is released in the spinal cord under inflammatory conditions that is likely to influence the synaptic processing.
Glutamate activates AMPA/kainate (non-N-methyl-D-aspartic acid (NMDA)) receptors and NMDA receptors. Both glutamate receptor types have been implicated in the generation and maintenance of inflammation-induced spinal hyperexcitability. Application of antagonists at AMPA/kainate and NMDA receptors prevents the development of hyperexcitability in the course of joint inflammation80 and muscle inflammation.8 Importantly, antagonists at both receptor types can also reduce responses of the neurons to mechanical stimulation of the joint after inflammation is established,80 even in a chronic model of inflammation.12 The excitatory neuropeptides facilitate the responses of spinal cord neurons to mechanical stimulation of joint and muscle, further the development of inflammation-evoked hyperexcitability, and "open" synaptic pathways such that more neurons respond to stimulation.8 However, antagonists at neuro-peptide receptors are less antinociceptive than antagonists at glutamate receptors.105,106,107 Topical application of PGE2 to the spinal cord surface facilitates the responses of spinal cord neurons to mechanical stimulation of the joint similar to knee joint inflammation.108 Topical application of the COX inhibitor indometacin to the spinal cord before inflammation attenuated the development of hyperexcitability.108 Thus spinal PGs are involved in inflammation-evoked spinal hyperexcitability.
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