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.
Abstracts of ICMART '98
International Medical Acupuncture Congress |
