Abstract
BackgroundMotor cortex stimulation (MCS) is an effective treatment in neuropathic pain refractory to pharmacological management. However, analgesia is not satisfactorily obtained in one third of patients. Given the importance of understanding the mechanisms to overcome therapeutic limitations, we addressed the question: what mechanisms can explain both MCS effectiveness and refractoriness? Considering the crucial role of spinal neuroimmune activation in neuropathic pain pathophysiology, we hypothesized that modulation of spinal astrocyte and microglia activity is one of the mechanisms of action of MCS.MethodsRats with peripheral neuropathy (chronic nerve injury model) underwent MCS and were evaluated with a nociceptive test. Following the test, these animals were divided into two groups: MCS-responsive and MCS-refractory. We also evaluated a group of neuropathic rats not stimulated and a group of sham-operated rats. Some assays included rats with peripheral neuropathy that were treated with AM251 (a cannabinoid antagonist/inverse agonist) or saline before MCS. Finally, we performed immunohistochemical analyses of glial cells (microglia and astrocytes), cytokines (TNF-α and IL-1β), cannabinoid type 2 (CB2), μ-opioid (MOR), and purinergic P2X4 receptors in the dorsal horn of the spinal cord (DHSC).FindingsMCS reversed mechanical hyperalgesia, inhibited astrocyte and microglial activity, decreased proinflammatory cytokine staining, enhanced CB2 staining, and downregulated P2X4 receptors in the DHSC ipsilateral to sciatic injury. Spinal MOR staining was also inhibited upon MCS. Pre-treatment with AM251 blocked the effects of MCS, including the inhibitory mechanism on cells. Finally, MCS-refractory animals showed similar CB2, but higher P2X4 and MOR staining intensity in the DHSC in comparison to MCS-responsive rats.ConclusionsThese results indicate that MCS induces analgesia through a spinal anti-neuroinflammatory effect and the activation of the cannabinoid and opioid systems via descending inhibitory pathways. As a possible explanation for MCS refractoriness, we propose that CB2 activation is compromised, leading to cannabinoid resistance and consequently to the perpetuation of neuroinflammation and opioid inefficacy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0216-1) contains supplementary material, which is available to authorized users.
Highlights
Motor cortex stimulation (MCS) is an effective treatment in neuropathic pain refractory to pharmacological management
As a possible explanation for MCS refractoriness, we propose that Cannabinoid type 2 receptor (CB2) activation is compromised, leading to cannabinoid resistance and to the perpetuation of neuroinflammation and opioid inefficacy
In an attempt to elucidate the modulation of glial cell activity in MCS-induced analgesia, we evaluated Iba-1 and glial fibrillary acidic protein (GFAP) immunolabeling in the dorsal horn of the spinal cord (DHSC) ipsilateral to the constriction injury (CCI)
Summary
Motor cortex stimulation (MCS) is an effective treatment in neuropathic pain refractory to pharmacological management. Classic symptoms include allodynia (pain in response to innocuous thermal or mechanical stimuli), hyperalgesia (exaggerated pain in response to noxious stimuli), and spontaneous pain (pain in the absence of noxious stimulation) [2,3,4] These symptoms can be explained by immunogenic and neurogenic mechanisms such as glial activation, proinflammatory cytokine release, and differential activation of receptors [3,5,6]. Proinflammatory cytokines, such as IL-1β and TNF-α, are secreted by activated astrocytes and microglia, enhancing glutamatergic transmission and disinhibiting GABAergic interneurons in the dorsal horn of the spinal cord (DHSC). Cannabinoid type 2 receptor (CB2) activation in glial cells decreases IL-1β and TNF-α release [7,10,11], while the binding of adenosine triphosphate (ATP) to purinergic P2X4 receptors in microglia leads to the secretion of inflammatory mediators [12]
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