Activation of spinal dorsal horn inhibitory networks by the CLTMR derived chemokine TAFA4

Pain elaboration results from the integration within dorsal spinal cord networks of sensory and nociceptive information conveyed by primary afferents. Among these, C low-threshold Mechano Receptors (CLTMRs), expressing the chemokine TAFA4, were recently identified as modulators of pain. Although TAFA4 was previously demonstrated to modulate pain transmission through the modulation of potassic IA-like currents in superficial dorsal horn neurons, the functional repercussions of this modulation on sensory-nociceptive integration remains poorly understood. In this study, we investigated the effects of TAFA4 on synaptic transmission in Rexed lamina IIi in dorsal horn. Using /in vitro/ patch clamp electrophysiology, we demonstrate that in WT mice, bath application of TAFA4 (20nM) induces a reversible increase in frequency of spontaneous GABAergic IPSCs. This modulation of synaptic activity was preserved with TTX, suggesting that TAFA4 alters synaptic transmission through presynaptic mechanisms. Using Electron Microscopy, we demonstrate the presence of direct synaptic contacts between CLTMR and GABAergic terminals within lamina IIi. We further demonstrate that this increase in inhibitory activity induces a decrease in the frequency of spontaneous EPSCs in control and in inflammatory condition. Furthermore, in inflammatory conditions, preliminary results suggest that in 1/3 of recorded neurons TAFA4 induces an increase in the paired pulse ratio of synaptic responses evoked by high intensity stimulation of dorsal roots, indicating reinforced presynaptic inhibition of nociceptive afferent neurons. Alltogether, we propose that CLTMRs directly contact inhibitory interneurons within dorsal spinal cord, and, through the liberation of TAFA4, reinforce inhibitory synaptic activity which may in turn promote their anti-nociceptive activity.