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. 2023 Apr 25;24(9):7796.
doi: 10.3390/ijms24097796.

Systemic and Peripheral Mechanisms of Cortical Stimulation-Induced Analgesia and Refractoriness in a Rat Model of Neuropathic Pain

Danielle V Assis  1 , Ana Carolina P Campos  1 , Amanda F N Paschoa  1 , Talita F Santos  1 , Erich T Fonoff  2 , Rosana L Pagano  1
Affiliations

Systemic and Peripheral Mechanisms of Cortical Stimulation-Induced Analgesia and Refractoriness in a Rat Model of Neuropathic Pain

Danielle V Assis et al. Int J Mol Sci. .

Abstract

Epidural motor cortex stimulation (MCS) is an effective treatment for refractory neuropathic pain; however, some individuals are unresponsive. In this study, we correlated the effectiveness of MCS and refractoriness with the expression of cytokines, neurotrophins, and nociceptive mediators in the dorsal root ganglion (DRG), sciatic nerve, and plasma of rats with sciatic neuropathy. MCS inhibited hyperalgesia and allodynia in two-thirds of the animals (responsive group), and one-third did not respond (refractory group). Chronic constriction injury (CCI) increased IL-1β in the nerve and DRG, inhibited IL-4, IL-10, and IL-17A in the nerve, decreased β-endorphin, and enhanced substance P in the plasma, compared to the control. Responsive animals showed decreased NGF and increased IL-6 in the nerve, accompanied by restoration of local IL-10 and IL-17A and systemic β-endorphin. Refractory animals showed increased TNF-α and decreased IFNγ in the nerve, along with decreased TNF-α and IL-17A in the DRG, maintaining low levels of systemic β-endorphin. Our findings suggest that the effectiveness of MCS depends on local control of inflammatory and neurotrophic changes, accompanied by recovery of the opioidergic system observed in neuropathic conditions. So, understanding the refractoriness to MCS may guide an improvement in the efficacy of the technique, thus benefiting patients with persistent neuropathic pain.

Keywords: inflammation; motor cortex stimulation; neuropathic pain; neurotrophins; sciatic nerve; substance P; β-endorphin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Experimental design, CCI induction, and MCS procedure. Temporal scheme of the procedures performed with the animals during the 14 days of experimentation. The timeline description: Day 0 represents the basal measurement of the nociceptive tests. Animals were submitted to the chronic constriction injury (CCI) of the right sciatic nerve, and false-operated animals (FOP) were used as control. Day 7, two transdural electrodes were placed on the primary motor cortex over the right hind limb area. Day 14, animals were initially divided into three experimental groups: FOP, CCI, and CCI + MCS. They were evaluated using nociceptive tests. CCI + MCS animals were submitted to 15 min of MCS and, still under stimulation, were reevaluated in the tests. After this 15 min of MCS, the third group was subdivided into CCI + MCS responsive or CCI + MCS refractory, totaling four experimental groups: FOP, CCI, CCI + MCS responsive and CCI + MCS refractory. FOP and unstimulated CCI animals were also reevaluated in the tests. After the last test, animals were euthanized, and the tissues were subjected to different assays. IM, initial measurement; intM, intermediate measurement; FM, final measurement. Adapted from “multi-panel vertical timeline” by BioRender.com, accessed on 1 September 2022.
Figure 2
Figure 2
Effect of MCS treatment on the hypernociception of animals with peripheral neuropathy. Animals were evaluated in the paw pressure test (A) and with von Frey filaments (B), to detect the mechanical hyperalgesia and allodynia, respectively, in the right paw, before any surgical intervention (initial measurement, IM), after 14 days of FOP or CCI (intermediate measurement, IntM) and 15 min after MCS, still under stimulation (final measurement, FM). FOP and unstimulated CCI animals were also evaluated (n = 10 animals/group). * p < 0.001 in relation to MI; # p < 0.05 in relation to IM and IntM. FOP, false-operated; CCI, chronic sciatic nerve constriction; CCI + MCS, stimulation of the motor cortex in animals with CCI.
Figure 3
Figure 3
Effect of MCS treatment on inflammatory and neurotrophic profile in the sciatic nerve of rats with peripheral neuropathy. Quantitative analysis of multiplex assay for TNF-α (A), IL-1β (B), IL-4 (C), IL-6 (D), IL-10 (E), IL-17 (F), IFNγ (G), CX3CL1 (H), and NGF (I) on the sciatic nerve of false-operated (FOP) rats, with peripheral neuropathy (CCI), with CCI responsive to MCS (CCI + MCS responsive), and with CCI refractory to MCS (CCI + MCS refractory) (n = 5 animals/group). * p < 0.05 compared to the FOP group. # p < 0.05 compared to the CCI group.
Figure 4
Figure 4
Effect of MCS treatment on the inflammatory and neurotrophic profile in the DRG of rats with peripheral neuropathy. Quantitative analysis of multiplex assay for TNF-α (A), IL-1β (B), IL-4 (C), IL-6 (D), IL-10 (E), IL-17 (F), IFNγ (G), and CX3CL1 (H) on the sciatic nerve of false-operated (FOP) rats, with peripheral neuropathy (CCI), with CCI responsive to MCS (CCI + MCS responsive), and with CCI refractory to MCS (CCI + MCS refractory) (n = 5 animals/group). * p < 0.05 compared to the FOP group. # p < 0.05 compared to the CCI group.
Figure 5
Figure 5
Pattern of circulating plasma biomarkers after MCS treatment. Expression analysis of SP (A), β-endorphin (B), and BDNF (C) on the plasma of false-operated rats (FOP), with peripheral neuropathy (CCI), with CCI responsive to MCS (CCI + MCS responsive), and with CCI refractory to MCS (CCI + MCS refractory) (n = 5 animals/group). * p < 0.05 compared to the FOP group. # p < 0.05 compared to the FOP and CCI group.
Figure 6
Figure 6
Representative illustration for the differential expression of factors involved in NP control against MCS responsiveness and refractoriness in rats. Didactic illustration of cytokines TNF-α, IL-1β, IL-4, IL-6, IL-10, IL-17A, IFNγ, and neurotrophin NGF expression in the sciatic nerve and DRG of false-operated (FOP, A) rats, with peripheral neuropathy (CCI, B), with CCI responsive to MCS (CCI + MCS responsive, C), and with CCI refractory to MCS (CCI + MCS refractory, D), as well as SP, β-endorphin, and BDNF expression in plasma of the same groups. DHSC: dorsal horn of the spinal cord.
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