Signalling in the Pain Matrix

W. Ziegelgaensgerger
Max Planck Institute of Psychiatry, Munich , Germany

The earliest short-term responses following nociceptor activation are reflected in rapid changes of neuronal discharge activity in a variety of pharmacologically and anatomically distinct systems in the central nervous system. In these systems long-term changes most commonly require alterations in gene expression. The activity-dependent modulation of gene expression is a characteristic feature of highly integrated systems such as the pain matrix. Each of the levels of integration of nociceptive information probably receives and is the origin of modulatory mechanisms conveyed by afferent segmental or descending pathways. Besides “classical” neurotransmitters, biologically active molecules such as peptide hormones, neurosteroids, adenosine, trophic factors or cytokines released synaptically or non-synaptically from terminals, neighbouring neurons, glia cells or components of the immune system or from the circulation participate in the integration of somatosensory information.

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. 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 stimulation and is reduced by morphine application before the stimulation. Protein phosphorylation of ligandgated channels appears as a major mechanism in the regulation of neuronal plasticity. The activation of protein kinases increases the responsiveness of dorsal horn neurons to L-glutamate and enhances NMDA-activated synaptic currents. NK1 receptor activation probably triggers the phosphorylation of NMDA receptors through phospholipase C stimulation. During inflammatory hyperalgesia NKl receptors and proteinkinases are up regulated and more tachykinins are released. In monoarthritic rats, glutamic acid-decarboxylase-mRNA increases in the spinal cord ipsilaterally to the inflammatory lesion. This enhancement is probably a direct consequence of a transsynaptic activation of the GABAergic neurons in the spinal cord. At analgesic doses systemically applied opioids activate spinal and supraspinal mechanisms via μ, k and the recently characterized orphan opioid receptors and prevent activity-dependent gene expression. Some of the discrete systems in the pain matrix appear sensitive to agents that were otherwise not predicted by traditional preclinical pain models as well as human pain states.