Transcript Slide 1
Primary afferents Presynaptic inhibition “is more powerful than postsynaptic inhibition in depressing the central excitatory actions of almost all primary afferent fibres”. (Eccles 1964) Large fibers DA reduces presynaptic inhibition of non-pain encoding primary afferents X DA ’s afferent input to dorsal horn neurons at stimulus intensities that activate nociceptors minutes Hernández-Rodríguez, Calvo, Hochman, Quevedo Garraway & Hochman 2001 DA inhibits pain and increases non-pain sensory info 1 DA release from A11 Electrical stimulation of A11 depresses nociceptive input to spinal cord dorsal horn neurons *A11 stim x noxious pinch spontaneous activity Fleetwood-Walker et al 1988 brush DLH *Substantia nigra (A9) stimulation – no effect 2 Isolated spinal cord with hindlimbs in a dish D2-like agonists block nociceptive response at the spinal cord level “A good means to discovery is to take away certain parts of a system and to find out how the rest behaves.” George Christoph Lichtenberg (1742-1799) Is this an important site of therapeutic action in RLS? Hayes & Hochman 3 Chronic changes in sensory function could lead to long-lasting changes in brain structures Cortical activity Thalamic activity Peripheral sensitization: Spinal cord excitability Peripheral nerve injury triggers long-term changes in excitatory synaptic transmission in the anterior cingulate cortex Xu et al 2008 4 Sympathetic preganglionics Entire CNS sympathetic neural output via spinal cord Sympathetic neurons IML IML Motoneurons 5 DA directly depresses sympathetic output and DA synthesis has a diurnal rhythm DA usually hyperpolarizes and depresses sympathetic activity DA synthesis in the IML has a diurnal rhythm Gladwell and Coote 1999 Coote et al 1981 Clemens, Sawchuk & Hochman 2005 6 Sympathetic innervation of muscle and adrenergic activation of muscle nociceptors Sympathetic innervation of muscle In vitro diaphragm-phrenic nerve preparation Kniffki et al 1978 Could an increased sympathetic drive aberrantly activate muscle nociceptors? 7 Motor systems Dopamine activates the spinal cord central pattern generator for locomotion Hayes Cheng & Hochman Kiehn and Kjærulff 1996 Is a facilitated DA drive contributing to PLMS? 8