The Pain Matrix

W. Zieglgansberger
Max Planck Institute of Psychiatry, Kraeppelinstr. 2, D-80804, Munich

Emerging knowledge related to the diversity of pain-related systems in the central and peripheral nervous systems suggests that besides "classical" neurotransmitters, e.g., L-glutamate, substance P, g-aminobutyric acid (GABA) and monoamines, biologically active molecules such as peptide hormones, neurosteroids, trophic factors or cytokines participate in the integration of somatosensory information in the pain matrix. These substances are released synaptically or non-synaptically from terminals, neighbouring neurons, glia cells or components of the immune system or from the circulation. These neuronal and hormonal systems, which act in concert to help the individual to cope with pain, have been detailed by the modern neurosciences.

By detailing the multiplicity of transducing and suppressive systems novel compounds and new regimes for drug treatment and afferent stimulation to prevent activity-dependent long-term changes are emerging. Chronic pain states arise from a variety of pharmacologically distinct systems which offer novel targets for selective pharmacotherapy and appear sensitive to families of agents that were otherwise not predicted by traditional preclinical pain models as well as human pain states.

The activation of a nociceptor in the peripheral tissue triggers sets of neuronal events which extend over a time frame ranging from milliseconds to hours, days or weeks. Most nociceptors in the peripheral tissue are polymodal: they respond to noxious heat, strong mechanical stimuli, and to a battery of exogenous and endogenous chemical stimuli (including prostaglandins, bradykinin, histamine, cytokines). These multimodal nociceptors can be sensitized by a number of factors released by the damaged tissue leading to primary hyperalgesia. Sensitization causes specific upregulation of expression of ion channels and receptors on these structures.

A major facilitatory effect of the central nervous system responding to noxious stimuli involves the interaction between L-glutamate and substance P, a neuropeptide long thought to have a role in pain perception. GABA is a major inhibitory neurotransmitter in the mammalian CNS and GABA binding sites and GABA containing neurons have been characterized in almost all pain-related structures. Even slight alterations in the excitability of multireceptive dorsal horn neurones (wide-dynamic-range, WDR neurones) can dramatically influence the size of their receptive fields measured in the peripheral tissue, i.e. the area in the periphery where a stimulus will trigger action potentials in this neuron. The excitatory receptive fields are most commonly surrounded by inhibitoty receptive fields. The size of the excitatory receptive field can be increased by the application of L-glutamate into the vicinity of these neurones and can be reduced in size by the application of the inhibitory neurotransmitter GABA. Repetitive electrical stimulation of the inhibitory receptive field can induce a longlasting suppression of neuronal discharge activity of WDR neurones. While the earliest short-term responses are reflected in rapid changes of neuronal discharge activity the long-term changes most commonly require alterations in gene expression. The importance of WDR neurones in the establishment of hyperalgesia and allodynia suggests a strategic focus for drug treatment or interventions by peripheral stimulation, e.g. by acupuncture or physical therapy, on this first stage of sensory integration in the CNS. Activity-dependent modulation of gene expression is a feature of highly integrated systems and greatly expands the capacity to react in a more plastic manner to environmental stimuli. Immediate-early-genes (IEGs) are thought to participate as third messengers in the late phase of the stimulus transcription cascade. They code for transcription factors and alter gene expression and translation into the corresponding protein products such as enzymes, receptors or neurotransmitters. The amount of several IEG-coded proteins, produced by central neurons, is proportional to the degree of synaptic excitation following somatic and visceral acute noxious.

Similar neuroplastic changes take place in other components of the pain matrix, e.g. in areas integrating pain treshold and intensity or its unpleasantness in the neocortex or subcortical limbic areas. Chronic inflammation or injury of peripheral nerves evokes the reorganization of cortical sensory maps. These recent advances in electrophysiological, molecular and cellular biological techniques have profoundly changed the face of pain research. The multitude of dynamic changes which occur during chronic pain states may also offer explanations for some of the effects observed following acupuncture and treatment with related techniques.

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