Non-classical control of body sensations

A. Non-classical mechanisms of presynaptic inhibition. Primary afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli. Somatosensory transmission is controlled by a unique ionotropic form of presynaptic inhibition that powerfully limits body sensations. Using multi-pronged approaches that include pioneering electrophysiological studies in the in vitro nerves-attached rodent spinal cord, we are challenging the deeply ingrained doctrine that a 3-synapse circuit with GABAergic interneurons acting on GABAA receptors is responsible. We identified the presence of more direct pathways (Shreckengost et al 2010). We also observed an underlying complex pharmacology that supports promiscuous blending of cys-loop receptors and questions the proprietary role of GABA and GABAA receptors in this process. Cholinergic transmission in particular may contribute significantly, including via direct release from primary afferents. ß-alanine and taurine transmission are also implicated (Hochman et al 2010).

B. Modulatory actions of serotonin, noradrenaline and dopamine. These neuromodulatory transmitters arise from descending systems to control spinal sensory integration. We provided the first comparative analysis of their actions on synaptic and cellular properties of spinal sensory encoding neurons (Garraway and Hochman 2001). These modulators acted in a comparable and predictable manner; to profoundly depress sensory input yet increase cell excitability. With Jorge Quevedo, in a just submitted manuscript, we looked more specifically at modulation of afferents arising from muscle and cutaneous nerves, and again found broadly uniform actions – depression of afferent input. My lab then looked at actions arising from visceral afferents, again observing broad depression. Yet, in all above studies, subtly different responses for each monoamine were seen. Thus, the different monoamines, recruited by different brain systems during different behavioral drives, all include the general feature of reducing body sensations, particularly pain. In contrast, the actions of the monoamines on motor systems are generally facilitatory, but also differentiable. For example, noradrenaline promotes self-reinforcing positive feedback in spinal motor circuits while serotonin promoted negative feedback (Machacek & Hochman 2006).