Impaired GABAergic inhibition in neuropathic pain

At the level of the spinal dorsal horn processing of nociceptive information is effectively controlled by inhibitory interneurons which use -aminobutyric acid (GABA) as a neurotransmitter. This inhibitory control is indispensable for normal pain sensitivity. It is generally believed that an impaired spinal GABAergic inhibition causes abnormal pain such as touch-evoked pain (allodynia) in neuropathic patients. The underlying mechanisms are, however, not fully understood. Now, transgenic mice are available which express the green fluorescent protein (EGFP) selectively in GABAergic neurons. This allows for the first time comprehensive studies on the properties and functions of these neurons. In this research proposal we plan to in investigate how spinal GABAergic neurons react to different forms of mononeuropathy of sciatic nerve induced either by chronic constriction injury or by spared nerve injury. The function of GABAergic neurons largely depends upon their input-output relationship. Thus, in neuropathic mice and in sham-treated animals we plan to compare the synaptic input to GABAergic neurons, their active and passive membrane properties and their discharge patterns. We expect that this project will provide new insights into the mechanisms of neuropathic pain and we hope that our work will open new avenues for the prevention and treatment of chronic pain.

Acute pain has an important homeostatic function. Under normal conditions the pain intensity correlates well with the intensity of a noxious stimulus. A proper correlation between both requires a delicate balance between excitation and inhibition within the nociceptive system of the spinal dorsal horn. In pain patients with a neuropathy the correlation between pain and a noxious stimulus may, however, virtually be lost. This leads to pain sensation by light touch or to spontaneous pain, i.e. to a pain sensation in the absence of any identifiable stimulus. It is an intriguing hypothesis that neuropathy may lead to an impaired inhibition in the spinal dorsal horn thereby shifting the balance towards excitation. In the present FWF research project we have thus studied principle functions of inhibition within the nociceptive system of the spinal dorsal horn. In general neuronal functions are determined by three key parameters: I. The excitatory and the inhibitory input to a given neuron. II. The neuronal excitability and III. The output functions of the neuron. We now demonstrate that in neuropathy the excitatory drive to identified inhibitory spinal dorsal horn neurons is globally impaired. Interestingly the neuronal excitability remains, in contrast, unchanged. This allows the conclusion that impaired excitation is faithfully translated into reduced inhibitory output in these spinal dorsal horn neurons. We and others have shown previously that reduced inhibition in spinal dorsal horn may cause spontaneous firing of nociceptive spinal dorsal horn neurons. Reduced spinal inhibition may in addition lead to a breakdown of functional borders between spinal cord areas which process touch-related information and those which process pain-related stimuli. Impaired inhibition in spinal dorsal horn thus likely contributes to both, spontaneous pain and to touch-evoked pain. Further, the output of any inhibitory neuron significantly depends upon the strength of inhibitory synapses, i.e. upon the efficacy of inhibitory contact sites between nerve cells. We have now identified a novel form of plasticity in spinal dorsal horn: the long-term potentiation at inhibitory synapses following strong noxious stimuli. This long- term potentiation is likely necessary to keep the critical balance intact between excitation and inhibition. It is presently unknown if neuropathy alters the long-term potentiation at inhibitory spinal synapses. This will be studied in a future project.