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Macrophage Activation in the Dorsal Root Ganglion in Rats Developing Autotomy after Peripheral Nerve Injury.

ABSTRACT: Autotomy, self-mutilation of a denervated limb, is common in animals after peripheral nerve injury (PNI) and is a reliable proxy for neuropathic pain in humans. Understanding the occurrence and treatment of autotomy remains challenging. The objective of this study was to investigate the occurrence of autotomy in nude and Wistar rats and evaluate the differences in macrophage activation and fiber sensitization contributing to the understanding of autotomy behavior. Autotomy in nude and Wistar rats was observed and evaluated 6 and 12 weeks after sciatic nerve repair surgery. The numbers of macrophages and the types of neurons in the dorsal root ganglion (DRG) between the two groups were compared by immunofluorescence studies. Immunostaining of T cells in the DRG was also assessed. Nude rats engaged in autotomy with less frequency than Wistar rats. Autotomy symptoms were also relatively less severe in nude rats. Immunofluorescence studies revealed increased macrophage accumulation and activation in the DRG of Wistar rats. The percentage of NF200+ neurons was higher at 6 and 12 weeks in Wistar rats compared to nude rats, but the percentage of CGRP+ neurons did not differ between two groups. Additionally, macrophages were concentrated around NF200-labeled A fibers. At 6 and 12 weeks following PNI, CD4+ T cells were not found in the DRG of the two groups. The accumulation and activation of macrophages in the DRG may account for the increased frequency and severity of autotomy in Wistar rats. Our results also suggest that A fiber neurons in the DRG play an important role in autotomy.

SUBMITTER: Xu X

PROVIDER: S-EPMC8657625 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDorsal root ganglion field stimulation is an analgesic neuromodulation approach in use clinically, but its mechanism is unknown as there is no validated animal model for this purpose. The authors hypothesized that ganglion stimulation is effective in reducing pain-like behaviors in preclinical chronic pain models.MethodsThe authors provided ganglion stimulation or spinal cord stimulation to rats with traumatic neuropathy (tibial nerve injury), or osteoarthritis induced by intraarticular knee monosodium iodoacetate, or without injury (naïve). Analgesia was evaluated by testing a battery of pain-related reflexive, functional, and affective behaviors.ResultsIn rats with nerve injury, multilevel L4 and L5 ganglion stimulation decreased hypersensitivity to noxious mechanical stimulation more (area under curve, -1,447 ± 423 min × % response; n = 12) than single level ganglion stimulation at L4 ([-960 ± 251 min × % response; n = 8; P = 0.012] vs. L4 and L5), and L5 ([-676 ± 295 min × % response; n = 8; P < 0.0001] vs. L4 and L5). Spontaneous pain-like behavior, evaluated by conditioned place preference, responded to single L4 (Pretest [-93 ± 65 s] vs. Test [87 ± 82 s]; P = 0.002; n = 9), L5 (Pretest [-57 ± 36 s] vs. Test [137 ± 73 s]; P = 0.001; n = 8), and multilevel L4 and L5 (Pretest: -81 ± 68 s vs. Test: 90 ± 76 s; P = 0.003; n = 8) ganglion stimulation. In rats with osteoarthritis, multilevel L3 and L4 ganglion stimulation reduced sensitivity to knee motion more (-156 ± 28 min × points; n = 8) than L3 ([-94 ± 19 min × points in knee bend test; n = 7; P = 0.002] vs. L3 and L4) or L4 ([-71 ± 22 min × points; n = 7; P < 0.0001] vs. L3 and L4). Conditioned place preference during osteoarthritis revealed analgesic effectiveness for ganglion stimulation when delivered at L3 (Pretest [-78 ± 77 s] vs. Test [68 ± 136 s]; P = 0.048; n = 9), L4 (Pretest [-96 ± 51 s] vs. Test [73 ± 111 s]; P = 0.004; n = 9), and L3 and L4 (Pretest [-69 ± 52 s; n = 7] vs. Test [55 ± 140 s]; P = 0.022; n = 7).ConclusionsDorsal root ganglion stimulation is effective in neuropathic and osteoarthritic preclinical rat pain models with peripheral pathologic origins, demonstrating effectiveness of ganglion stimulation in a placebo-free setting and justifying this model as a suitable platform for mechanistic studies.

Project description:BackgroundNeuropathic pain is an apparently spontaneous experience triggered by abnormal physiology of the peripheral or central nervous system, which evolves with time. Neuropathic pain arising from peripheral nerve injury is characterized by a combination of spontaneous pain, hyperalgesia and allodynia. There is no evidence of this type of pain in human infants or rat pups; brachial plexus avulsion, which causes intense neuropathic pain in adults, is not painful when the injury is sustained at birth. Since infants are capable of nociception from before birth and display both acute and chronic inflammatory pain behaviour from an early neonatal age, it appears that the mechanisms underlying neuropathic pain are differentially regulated over a prolonged postnatal period.ResultsWe have performed a microarray analysis of the rat L4/L5 dorsal root ganglia (DRG), 7 days post spared nerve injury, a model of neuropathic pain. Genes that are regulated in adult rats displaying neuropathic behaviour were compared to those regulated in young rats (10 days old) that did not show the same neuropathic behaviour. The results show a set of genes, differentially regulated in the adult DRG, that are principally involved in immune system modulation. A functional consequence of this different immune response to injury is that resident macrophages cluster around the large A sensory neuron bodies in the adult DRG seven days post injury, whereas the macrophages in young DRG remain scattered evenly throughout the ganglion, as in controls.ConclusionsThe results show, for the first time, a major difference in the neuroimmune response to nerve injury in the dorsal root ganglion of young and adult rats. Differential analysis reveals a new set of immune related genes in the ganglia, that are differentially regulated in adult neuropathic pain, and that are consistent with the selective activation of macrophages around adult, but not young large A sensory neurons post injury. These differences may contribute to the reduced incidence of neuropathic pain in infants.

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Macrophage Activation in the Dorsal Root Ganglion in Rats Developing Autotomy after Peripheral Nerve Injury.

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