title: The spinal anti-inflammatory mechanism of motor cortex stimulation: cause of success and refractoriness in neuropathic pain?
abstract: BACKGROUND
  Motor 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.
  
  
  METHODS
  Rats 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).
  
  
  RESULTS
  MCS 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Laboratory of Neuromodulation and Experimental Pain, Hospital Sírio Libanês, Rua Coronel Nicolau dos Santos, 69, 01308-060, São Paulo, SP, Brazil. guilherme.diogo.silva@usp.br.
authors.forename: Guilherme D
authors.initials: GD
authors.lastname: Silva
authors.affiliation: Laboratory of Neuromodulation and Experimental Pain, Hospital Sírio Libanês, Rua Coronel Nicolau dos Santos, 69, 01308-060, São Paulo, SP, Brazil. patriciasanae@hotmail.com.
authors.forename: Patrícia S S
authors.initials: PS
authors.lastname: Lopes
authors.affiliation: Laboratory of Neuromodulation and Experimental Pain, Hospital Sírio Libanês, Rua Coronel Nicolau dos Santos, 69, 01308-060, São Paulo, SP, Brazil. fonoffet@usp.br.|Division of Functional Neurosurgery, Department of Neurology, University of São Paulo School of Medicine, Rua Dr Ovídio Pires de Campos, 785, 01060-970, São Paulo, SP, Brazil. fonoffet@usp.br.
authors.forename: Erich T
authors.initials: ET
authors.lastname: Fonoff
authors.affiliation: Laboratory of Neuromodulation and Experimental Pain, Hospital Sírio Libanês, Rua Coronel Nicolau dos Santos, 69, 01308-060, São Paulo, SP, Brazil. rosana.lpagano@hsl.org.br.
authors.forename: Rosana L
authors.initials: RL
authors.lastname: Pagano
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D046690:Deep Brain Stimulation / Q000379:methods*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000209:etiology / Q000628:therapy; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009044:Motor Cortex / Q000187:drug effects / Q000502:physiology*; D009187:Myelitis / Q000209:etiology* / Q000628:therapy*; D009437:Neuralgia / Q000150:complications* / Q000473:pathology / Q000628:therapy; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000009:adverse effects; D011720:Pyrazoles / Q000009:adverse effects; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D058848:Receptors, Purinergic P2X4 / Q000378:metabolism
chemical_list: C100745:Aif1 protein, rat; D000893:Anti-Inflammatory Agents; D002135:Calcium-Binding Proteins; C469526:Cnr2 protein, rat; D016207:Cytokines; D008840:Microfilament Proteins; D010880:Piperidines; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; D017450:Receptors, Opioid, mu; D058848:Receptors, Purinergic P2X4; C103505:AM 251