• Jorge Vicente-Baz, Jose Antonio Lopez-Garcia, and Ivan Rivera-Arconada.
• Department of Systems Biology (Physiology), Universidad de Alcala, Alcala de Henares, Madrid, Spain.
• Eur J Pain. 2022 Feb 1; 26 (2): 356-369.

BackgroundAxo-axonic contacts onto central terminals of primary afferents modulate sensory inputs to the spinal cord. These contacts produce primary afferent depolarization (PAD), which serves as a mechanism for presynaptic inhibition, and also produce dorsal root reflexes (DRRs), which may regulate the excitability of peripheral terminals and second order neurons. We aimed to identify changes in these responses as a consequence of peripheral inflammation.MethodsIn vitro spinal cord recordings of spontaneous activities in dorsal and ventral roots were performed in control mice and following paw inflammation. We also used pharmacological assays to define the neurotransmitter systems implicated in such responses.ResultsPaw inflammation increased the frequency and amplitude of spontaneous dorsal root depolarizations, the occurrence of DRRs and the amplitude of ventral roots depolarizations. PAD was classified in two different patterns based on their relation to ventral activity: time-locked and independent events. Both patterns increased in amplitude after paw inflammation, and independent events also increased in frequency. The circuits that were responsible for this activity implicated both glutamatergic and GABAergic transmission. Adrenergic modulation differentially affected both types of PAD, and this modulation changed after paw inflammation.ConclusionsOur findings suggest the existence of independent spinal circuits at the origin of PAD and DRRs. Inflammation modulates these circuits differentially, unveiling varied mechanisms of spinal sensitization. This in vitro approach provides an isolated model for the study of the mechanisms of central sensitization and for the performance of pharmacological assays with the purpose of identifying and testing novel antinociceptive targets.SignificanceSpinal circuits modulate activity of primary afferents acting on central terminals. Under in vitro conditions, dorsal roots show spontaneous activity in the form of depolarizations and action potentials. Our findings are consistent with the existence of several independent generator circuits. Experimental paw inflammation reduced mechanical withdrawal threshold and significantly increased the spontaneous activity of dorsal roots, which may be secondary to an enhanced output of spinal generators. This can be considered as a novel sign of central sensitization.© 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.

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