Central sensitization of dorsal root potentials and dorsal root reflexes: An in vitro study in the mouse spinal cord.

Abstract

Background: Axo-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. Methods: In vitro spinal cord recordings of spontaneous activities in dorsal andventral roots were performed in control mice and following paw inflammation.We also used pharmacological assays to define the neurotransmitter systems implicated in such responses.Results: Paw 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. Conclusions: Our 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.Significance: Spinal 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

Synchronous firing of dorsal horn neurons at the origin of dorsal root reflexes in naïve and paw-inflamed mice

“…Both of these predictions from our interpretation have been proved experimentally. Inflammatory treatment has been shown to increase the production of dorsal root reflexes in vivo and in vitro (Lin et al, 2000;Vicente-Baz et al, 2022) as well as to potentiate spontaneous activity in dorsal horn neurons (Zain and Bonin, 2019). This interpretation of results places firing synchrony at the center of the mechanisms mediating central sensitization.…”

“…As previously discussed, peripheral inflammation leads to an increase in the backfiring of nociceptive primary afferents (Lin et al, 2000). We have shown recently that this enhanced activity caused by peripheral inflammation develops quickly and persists in the isolated spinal cord demonstrating that the mechanisms underlying backfiring of the afferents are contained within the cord (Vicente-Baz et al, 2022). Therefore, as a secondary objective we aimed at evaluating the impact of a peripheral inflammation on synchronous activity of dorsal horn neurons.…”

Myofascial Pain as an Unseen Comorbidity in Osteoarthritis

“…For example, a persistent nociceptive input to small diameter afferents at the OA joint may lead to increased neuronal firing, persistent nociception, and segmental sensitization in the CNS 81,82. This may incite an antidromic reflex neurogenic inflammation and the release of neurogenic substances (eg, substance P, calcitonin gene-related peptide) toward the peripherally neurologically supplied skeletal muscle and joint tissues by the common spinal sensitized segment 77,83–87. This hypothesis has been tested in preclinical studies with the observation of increased neurogenic-related peptides, inflammation, and fibrosis skeletal muscle in segmentally related skeletal muscle;81,82,85,88,89 future studies are required to explore this alternate mechanism in humans.…”

“…81,82 This may incite an antidromic reflex neurogenic inflammation and the release of neurogenic substances (eg, substance P, calcitonin gene-related peptide) toward the peripherally neurologically supplied skeletal muscle and joint tissues by the common spinal sensitized segment. 77,[83][84][85][86][87] This hypothesis has been tested in preclinical studies with the observation of increased neurogenic-related peptides, inflammation, and fibrosis skeletal muscle in segmentally related skeletal muscle; 81,82,85,88,89 future studies are required to explore this alternate mechanism in humans. Importantly, to the best of our knowledge, no experimental studies have been designed to examine the effects of an OA disease-modifying treatment on MPS and MTrPs-related outcomes.…”

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders

“…However, the future direction of KCNQ neural mechanosensation literature ought to focus more on the clinical and translational use of these pharmacotherapeutic options, as most of the literature used to support this review was based on animal models alone. Despite this, there is strong evidence that could support the initiation of future clinical trials, especially for auditory pathologies as well as in PD [ 14 , 80 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 ], and developments for understanding the effects that antimicrobial agents have on these potassium ion channels [ 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 ]. Additionally, the scope of this review was on neural modulation, yet there is a growing amount of literature on the behavior of KCNQ channels in cardiac modulations as well, especially in the cellular processes involved in arrhythmia [ 26 , 27 , 28 , 29 , 139 , 140 , 141 ,…”