Abstract
Amputation of a sensory peripheral nerve induces severe anatomical and functional changes along the afferent pathway as well as perception alterations and neuropathic pain. In previous studies we showed that electrical stimulation applied to a transected infraorbital nerve protects the somatosensory cortex from the above-mentioned sensory deprivation-related changes. In the present study we focus on the initial tract of the somatosensory pathway and we investigate the way weak electrical stimulation modulates the neuroprotective-neuroregenerative and functional processes of trigeminal ganglia primary sensory neurons by studying the expression of neurotrophins (NTFs) and Glia-Derived Neurotrophic Factors (GDNFs) receptors. Neurostimulation was applied to the proximal stump of a transected left infraorbitary nerve using a neuroprosthetic micro-device 12 h/day for 4 weeks in freely behaving rats. Neurons were studied by in situ hybridization and immunohistochemistry against RET (proto-oncogene tyrosine kinase “rearranged during transfection”), tropomyosin-related kinases (TrkA, TrkB, TrkC) receptors and IB4 (Isolectin B4 from Griffonia simplicifolia). Intra-group (left vs. right ganglia) and inter-group comparisons (between Control, Axotomization and Stimulation-after-axotomization groups) were performed using the mean percentage change of the number of positive cells per section [100∗(left–right)/right)]. Intra-group differences were studied by paired t-tests. For inter-group comparisons ANOVA test followed by post hoc LSD test (when P < 0.05) were used. Significance level (α) was set to 0.05 in all cases. Results showed that (i) neurostimulation has heterogeneous effects on primary nociceptive and mechanoceptive/proprioceptive neurons; (ii) neurostimulation affects RET-expressing small and large neurons which include thermo-nociceptors and mechanoceptors, as well as on the IB4- and TrkB-positive populations, which mainly correspond to non-peptidergic thermo-nociceptive cells and mechanoceptors respectively. Our results suggest (i) electrical stimulation differentially affects modality-specific primary sensory neurons (ii) artificial input mainly acts on specific nociceptive and mechanoceptive neurons (iii) neuroprosthetic stimulation could be used to modulate peripheral nerve injuries-induced neuropathic pain. These could have important functional implications in both, the design of effective clinical neurostimulation-based protocols and the development of neuroprosthetic devices, controlling primary sensory neurons through selective neurostimulation.
Highlights
Peripheral nerve injuries directly affect primary sensory neurons inducing structural and functional alterations to the cell bodies of the damaged axons
In previous works we showed that chronic neuroprosthetic stimulation of amputated peripheral nerves preserves the somatosensory cortex from the physiological, anatomical, FIGURE 1 | (A,B) Schematic representation of the distributions of TG neurons according to the expression of their receptors. (A) Approximately 65% of trigeminal neurons are thermo-nociceptors; half of them express TrkA and the rest are Isolectin B4 (IB4) positive
To test our hypotheses we investigated the expression of neurotrophic factors’ binding receptors of TG primary sensory neurons following infraorbital nerve axotomy and electrical stimulation and we compared it with the expression in TG cells after infraorbital nerve axotomy and non-manipulated infraorbital nerve
Summary
Peripheral nerve injuries directly affect primary sensory neurons inducing structural and functional alterations to the cell bodies of the damaged axons. Neurons switch from “transmitting” to “repairing/growing” functional mode. At this stage cellular metabolism is mainly committed to the repair of the damaged structures, promoting axonal regeneration through the expression of growth-associated proteins, tubulin, actin, neuropeptides, and cytokines (Fu and Gordon, 1997; Boyd and Gordon, 2003). Phenotypic integrity of adult ganglion neurons is determined by both, anterograde, and retrograde communication with their target tissues (Hamburger and LeviMontalcini, 1949; Delcroix et al, 2003; Hippenmeyer et al, 2004) regeneration and repair processes are probably triggered only by retrograde communication signals from the injured periphery (Lundborg, 2005)
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