Learning and Memory in Pain Pathways
|Department of Neurophysiology, Center for Brain Research, Medical University of Vienna , Austria|
Recently, cellular and network mechanism have been identified in the spinal cord which function as an amplifier for pain-related information and which likely contributes to abnormal sensitivity to pain during inflammation.
Normal sensitivity to pain is required to identify potential harmful stimuli or tissue damage and to trigger the appropriate behavioral responses. Parts of the peripheral and the central nervous systems are dedicated to serve this function (Willis and Coggeshall, 2004) . The pain sensors are specialized nerve fibers which are present in almost all tissues and which can normally only be activated by strong, i.e. painful (noxious) stimuli. These pain sensing nerve fibers are called nociceptive C-fibers. Pain-related information is transmitted from nociceptive C-fibers to nerve cells in spinal cord which relay information to various brain areas. The final result of this chain of excitation is a multidimensional pain experience which is includes aversive, vegetative and sensory-discriminative aspects of pain.
Pain perception may be amplified during trauma, inflammation or nerve injury so that normally non painful stimuli, e.g. movement of a joint, muscle contraction, gentle touch of the skin or even normal body temperature cause pain. Moderate pain stimuli may then trigger excruciating pain sensations. It has long been recognized that sensitization of nociceptive C-fibers in the area of trauma or inflammation causes pain amplification. This “peripheral sensitization” typically ceases when the underlying inflammation has healed. In some unfortunate pain patients the abnormal pain sensitivity may, however, persist months and even years after the primary cause for pain has disappeared. Then pain is no longer a symptom of a disease but has become a disease in its own right–the “pain disease”–. A number of studies suggest that beside peripheral sensitization other pain amplifier must exist in the central nervous system, most likely in the spinal cord and that these central pain amplifiers may cause the pain disease (Nichols et al., 1999) . The neuronal mechanism(s) of central pain amplification are, however, not well understood.
Nerve cells, including nociceptive nerve fibers and spinal cord nerve cells communicate with each other at specialized junctions, the so called synapses, by using one or more chemical neurotransmitter(s) (Jonas et al., 1998) . We have reported recently that information transfer from C-fibers to a distinct group of nerve cells in superficial spinal dorsal horn is augmented in an activity-dependent manner (Ikeda et al., 2003) . After brief (seconds), high frequency (around 100 Hz) burst-like discharges in C-fibers synaptic information transfer is potentiated for prolonged periods of time (synaptic long-term potentiation, LTP). This form of LTP has been considered a potential spinal pain amplifier. However, trauma and inflammation cause ongoing, low frequency (1-10 Hz) discharges in C-fibers rather than brief, burst-like activity. Low frequency activity has been found to depress, rather than to augment information transfer between nerve cells at all synapses tested so far in the brain or spinal cord. Consequently, the concept of synaptic LTP as a spinal pain amplifier has been challenged. We reported recently (Ikeda et al., 2006) that information transfer between C-fibers and a distinct subgroup of nerve cells in superficial spinal dorsal horn is drastically amplified by low frequency (2 Hz) ongoing discharges in C-fibers both, in vitro and in vivo. We further show that also a natural afferent barrage during inflammation causes synaptic LTP in pain pathways in intact animals. This finding is important as electrical nerve stimulation which has been used in almost all studies to induce LTP leads to regular, synchronized discharges in all C-fibers of a nerve. In striking contrast, trauma or inflammation causes highly irregular non synchronized activity in a subset of C-fibers. We found that the spinal nerve cells which amplify pain-related information after high frequency bursts (e.g. after nerve injury) are different from those nerve cells which do so after ongoing low frequency discharges (e.g. during inflammation). These distinct cell populations project to different brain areas. The neurotransmitters, binding sites and cellular enzymes which mediate high- or low-frequency-induced LTP do, however, largely overlap. This is in line with previous findings showing that the very same mediators are important for exaggerated pain behavior in animals after nerve injury or inflammation. A notable exception is nitric oxide (NO) which is required for low-frequency-induced LTP only. NO is a gaseous signaling molecule which may freely diffuse through cells and tissue once produced. This molecule may spread the pain message to distant sites. Our results suggest that depending on the nature of injury or disease, and thus the pattern and frequency of discharges in sensory nerve fibers, distinct spinal nerve cell populations with different projection areas in the brain may function as pain amplifiers. Some of the projection areas of these spinal nerve cells are important for the aversive aspects of pain, while others trigger vegetative responses to pain. If these distinct spinal pain amplifiers also exist in human pain patients our findings may explain the very different pain characteristics which are typical for pain during inflammation or after a nerve injury. Our findings may help to develop better strategies for the prevention and therapy of different forms of pain. The new vistas on central pain amplifiers are more directed and more promising than ever.
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