Presynaptic inhibition of optogenetically identified VGIuT3+ sensory fibres by opioids and baclofen

Distinct subsets of sensory nerve fibres are involved in mediating mechanical and thermal pain hypersensitivity. They may also differentially respond to analgesics. Heat-sensitive C-fibres, for example, are thought to respond to mu-opioid receptor (MOR) activation while mechanoreceptive fibres are supposedly sensitive to delta-opioid receptor (DOR) or GABA(B) receptor (GABA(B)R) activation. The suggested differential distribution of inhibitory neurotransmitter receptors on different subsets of sensory fibres is, however, heavily debated. In this study, we quantitatively compared the,degree of presynaptic inhibition exerted by opioids and the GABABR agonist baclofen on (1) vesicular glutamate transporter subtype 3-positive (VGIuT3(+)) non-nociceptive primary afferent fibres and (2) putative nociceptive C-fibres. To investigate VGIuT3+ sensory fibres, we evoked excitatory postsynapti currents with blue light at the level of the dorsal root ganglion (DRG) in spinal cord slices of mice, expressing channelrhodopsin-2. Putative nociceptive C-fibres were explored in VGIuT3-knockout mice through electrical stimulation. The MOR agonist DAMGO strongly inhibited both VGIuT3(+) and VGIuT3-C-fibres innervating lamina I neurons but generally had less influence on fibres innervating lamina II neurons. The DOR agonist SNC80 did not have any pronounced effect on synaptic transmission in any fibre type tested, Baclofen, in striking contrast, powerfully inhibited all fibre populations investigated. In summary, we report optogenetic stimulation of DRG neurons in spinal slices as a capable approach for the subtype-selective investigation of primary afferent nerve fibres. Overall, pharmacological accessibility of different subtypes of sensory fibres considerably overlaps, indicating that MOR, DOR, and GABA(B)R expressions are not substantially segregated between heat and mechanosensitive fibres.