Descending noradrenergic controls of spinal nociceptive synaptic transmission

The nucleus locus coeruleus (LC) is a major source of noradrenergic projections to the spinal dorsal horn. There is considerable evidence that the bulbo spinal noradrenergic system plays a significant role in pain modulation. In the superficial dorsal horn of the spinal cord, noradrenaline was reported to act on the presynaptic terminals of primary afferent fibers (A delta and C fibers) to reduce glutamate release, and on the presynaptic terminals of inhibitory inter neurons to facilitate GABA and glycine releases. Furthermore, it produces an outward current postsynaptically by the activation of potassium channels. Recently, we developed an in vivo patch-clamp recording technique from LC neurons to study the modulatory role at the synaptic level. Male adult rats were anesthetized with urethane and the animal was fixed in a stereotaxic frame. After a craniotomy was performed, the cerebellum was removed to expose the dorsal surface of the brain stem. The patch pipette was advanced into the LC by using a micromanipulator. After established a gigaohm seal formation, cellattached and whole-cell patch-clamp recordings were made from LC neurons under current-and voltage-clamp conditions. Under cell-attached conditions, LC neuron tested fired spontaneously. Cutaneous noxious stimuli applied to the contralateral hindpaw transiently increased the frequency of the spontaneous action potentials. Under current-clamp conditions, the resting membrane potential was ranged from -45 to -60 mV, and spontaneous firing was also detected at the similar frequency compared with those obtained from cellattached and extracellular recordings. Under voltage-clamp conditions at a holding potential of-70 mV, LC neurons exhibited spontaneous excitatory postsynaptic currents (EPSCs). Spontaneous inhibitory postsynaptic currents (IPSCs) could be recorded at a holding potential of 0 mV. This newly-developed recording technique, thus enabled us to analyze in detail excitatory and inhibitory synaptic responses evoked in LC neurons in vivo and is therefore useful to elucidate the synaptic transmission in the LC in response to natural noxious stimulation and the plastic changes occurred in chronic pain models.