Consequences of the ablation of nonpeptidergic afferents in an animal model of trigeminal neuropathic pain (original) (raw)
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Background: The neurotrophin Nerve Growth factor (NGF) is known to influence the phenotype of mature nociceptors, for example by altering synthesis of neuropeptides, and changes in NGF levels have been implicated in the pathophysiology of chronic pain conditions such as neuropathic pain. We have tested the hypothesis that after partial nerve injury, NGF accumulates within the skin and causes ‘pro-nociceptive’ phenotypic changes in the remaining population of sensory nerve fibres, which could underpin the development of neuropathic pain. Results: Eleven days after chronic constriction injury of the rat mental nerve the intra-epidermal nerve fibre density of the chin skin from had reduced from 11.6 ± 4.9 fibres/mm to 1.0 ± 0.4 fibres/mm; this slowly recovered to 2.4 ± 2.0 fibres/mm on day 14 and 4.0 ± 0.8 fibres/mm on day 21. Cold hyperalgesia in the ipsilateral lower lip was detectable 11 days after chronic constriction injury, although at this time skin [NGF] did not differ between sides. At 14 days post-injury, there was a significantly greater [NGF] ipsilaterally compared to contralaterally (ipsilateral = 111 ± 23 pg/mg, contralateral = 69 ± 13 pg/mg), but there was no behavioural evidence of neuropathic pain at this time-point. By 21 days post-injury, skin [NGF] was elevated bilaterally and there was a significant increase in the proportion of TrkA-positive (the high-affinity NGF receptor) intra-epidermal nerve fibres that were immunolabelled for the neuropeptide Calcitonin Gene-related peptide. Conclusions: The temporal mismatch in behaviour, skin [NGF] and phenotypic changes in sensory nerve fibres indicate that increased [NGF] does not cause hyperalgesia after partial mental nerve injury, although it may contribute to the altered neurochemistry of cutaneous nerve fibres.
Sprouting of A-fibre primary afferents into lamina II in two rat models of neuropathic pain
Following peripheral nerve section, injured sensory A-fibres sprout into lamina II of the dorsal horn and form aberrant functional synapses. Such structural changes may underlie some of the sensory abnormalities observed in nerve-injured patients, including neuropathic pain. This study compared the ability of intact and injured A-fibres to sprout in two experimental models of neuropathic pain, where the onset and presence of abnormal behaviours indicative of neuropathic pain have been well described. Rats received either a unilateral chronic constriction injury of the sciatic nerve (CCI) or lesion of the L5 spinal nerve (SNL). The central distribution of the injured and uninjured afferents labelled with choleragenoid conjugated to horseradish peroxidase (B-HRP) was examined at different postoperative survival times. In both models, the contralateral uninjured side, used for control nerve or ganglion injections, showed labelling of the L3-6 spinal segments in laminae I, III-V, leaving lamina II unlabelled. In CC1 rats, injured sciatic afferents sprouted in lamina II of the L4-5 dorsal horn by 10 days postinjury. In SNL rats, injured L5 afferents sprouted into lamina II of the L45 dorsal horn by 24 h postinjury and were robust from 3 to 10 days. In both models, the labelling in lamina II was absent by 4 months. Labelling of the adjacent uninjured saphenous or intact L4 spinal nerve afferents did not reveal A-fibre sprouting. As the time-course of sprouting of injured A-fibres parallels the previously described behaviour interpreted as neuropathic pain in these models, this may be a phenomenon that contributes to sensory abnormalities such as ongoing pain and mechanical hypersensitivity.
Neuroscience Letters, 1990
Unilateral tight tigation of about half of the sciatic nerve in rats rapidly produces sympathetically dependent neuropathic pain which lasts many months and resembles causalgia in humans. The sensory abnormalities detected at the plantar side of the hindpaws include: (1) nocifensive responses to repetitive light touch (allodynia); (2) bilateral reduction in withdrawal thresholds to repetitive von-Frey hair stimulation (mechanical hyperesthesia); (3) bilateral reduction in withdrawal thresholds to CO2 laser heat pulses; and (4) unilateral increase in response duration to an intense laser heat pulse (thermal hyperalgesia). Using neonatal capsaicin treatment, we determined the type of afferent fiber remaining in the partially injured nerve, which mediates these disorders. Capsaicin, which destroys most C-and some A6-fibers in peripheral nerves, had no effect on the touch-evoked allodynia and mechanical hyperesthesia that are produced by partial sciatic nerve injury. These disorders were, therefore, mediated by myelinated fibers. In contrast, thermal hyperalgesia failed to develop in capsaicin-treated rats following partial nerve injury. Thus, thermal hyperalgesia produced by partial nerve injury appears to be mediated by heat-nociceptive C-fibers.
Pharmaceuticals
Neuropathic pain in humans arises as a consequence of injury or disease of somatosensory nervous system at peripheral or central level. Peripheral neuropathic pain is more common than central neuropathic pain, and is supposed to result from peripheral mechanisms, following nerve injury. The animal models of neuropathic pain show extensive functional and structural changes occurring in neuronal and non-neuronal cells in response to peripheral nerve injury. These pathological changes following damage lead to peripheral sensitization development, and subsequently to central sensitization initiation with spinal and supraspinal mechanism involved. The aim of this narrative review paper is to discuss the mechanisms engaged in peripheral neuropathic pain generation and maintenance, with special focus on the role of glial, immune, and epithelial cells in peripheral nociception. Based on the preclinical and clinical studies, interactions between neuronal and non-neuronal cells have been desc...
The Journal of Neuroscience, 1999
Mice that overexpress nerve growth factor (NGF-OE) in the skin have double the normal number of cutaneous sensory neurons, have increased innervation of the skin and spinal cord, and are hyperalgesic. Here, we have asked whether the increased cutaneous NGF level results in a selective survival of only certain functional types of neurons and whether it changes the properties of cutaneous neurons. Using electron microscopy, we show that the number of both myelinated and unmyelinated nociceptors increases substantially in NGF-OE mice by a factor of 3.3 and 1.5, respectively. Using extracellular recordings from single units, we demonstrate that large myelinated (Aβ) fibers are unchanged in prevalence and receptive properties. In contrast, among thin myelinated (Aδ) fibers, the percentage of nociceptors increased from a normal 65 to 97%, consistent with a selective survival of nociceptors during embryogenesis. These afferents showed a twofold increase in their mechanical responsiveness, ...
Experimental Neurology, 2015
Mirror-image pain is a phenomenon in which unprovoked pain is detected on the uninjured contralateral side after unilateral nerve injury. Although it has been implicated that enhanced production of nerve growth factor (NGF) in the contralateral dorsal root ganglion is important in the development of mirror-image pain, it is not known if this is related to enhanced expression of nociceptive fibers in the contralateral skin. Mechanical and thermal sensitivity in the contralateral hind paw was measured at four different time points (5, 10, 20 and 30 weeks) after transection and immediate end-to-end reconstruction of the sciatic nerve in rats. These findings were compared to the density of epidermal (peptidergic and non-peptidergic) nerve fibers on the contralateral hind paw. Mechanical hypersensitivity of the contralateral hind paw was observed at 10 weeks PO, a time point in which both subgroups of epidermal nerve fibers reached control values. Thermal hypersensitivity was observed with simultaneous increase in the density of epidermal peptidergic nerve fibers of the contralateral hind paw at 20 weeks PO. Both thermal sensitivity and the density of epidermal nerve fibers returned to control values 30 weeks PO. We conclude that changes in skin innervation and sensitivity are present on the uninjured corresponding side in a transient pain model. Therefore, the contralateral side cannot serve as control. Moreover, the current study confirms the involvement of the peripheral nervous system in the development of mirror-image pain.