title: Exploration of supraspinal mechanisms in effects of spinal cord stimulation: role of the locus coeruleus.
abstract: The neurobiological mechanisms of spinal cord stimulation (SCS) when applied for neuropathic pain are still incompletely known. Previous research indicates that brainstem circuitry is pivotal for the SCS effect. The present study aims at exploring the possible contribution to the SCS effects of the pain controlling system emanating from the locus coeruleus (LC) in the brain stem. Experiments were performed on the rat-spared nerve injury pain model. After evaluation of the attenuation of mechanical hypersensitivity induced by SCS, the effects of SCS on neuronal activity in the LC and on the noradrenaline (NA) content in the dorsal spinal cord were analyzed. SCS produced a significant increase in the discharge rate of LC neurons only in rats behaviorally responding to SCS as compared to non-responding and control animals. The NA content in the dorsal quadrant of the spinal cord ipsilateral to the nerve injury was analyzed using enzyme-linked immunosorbent assay in responding, non-responding and intact control rats both immediately following SCS and without SCS. No differences were found between these groups. In awake animals, lidocaine silencing of the ipsilateral LC or blocking of spinal noradrenergic system by intrathecal administration of α1,2 adrenoceptor antagonists failed to influence the antihypersensitivity effect of SCS. The present results indicate that the SCS-induced control of hypersensitivity in an experimental animal model of peripheral neuropathic pain may not be explained by the activation of direct spinal projections of noradrenergic LC neurons, while supraspinal projections of LC neurons still may play a role in the SCS effect.
authors.affiliation: Department of Clinical Neuroscience, Section of Neurosurgery, Karolinska Institutet, SE 171 76 Stockholm, Sweden. Electronic address: zhiyang.song@ki.se.
authors.forename: Z
authors.initials: Z
authors.lastname: Song
authors.forename: O B
authors.initials: OB
authors.lastname: Ansah
authors.forename: B A
authors.initials: BA
authors.lastname: Meyerson
authors.forename: A
authors.initials: A
authors.lastname: Pertovaara
authors.forename: B
authors.initials: B
authors.lastname: Linderoth
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006930:Hyperalgesia / Q000503:physiopathology / Q000628:therapy; D007093:Imidazoles / Q000494:pharmacology; D008012:Lidocaine / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology; D010812:Physical Stimulation / Q000009:adverse effects; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012585:Sciatica / Q000628:therapy*; D013116:Spinal Cord / Q000502:physiology*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D000779:Anesthetics, Local; D007093:Imidazoles; C050701:atipamezole; D008012:Lidocaine; D011224:Prazosin
keywords: -spared nerve injury; 3-methoxy-4-hydorxyphenethyleneglycol; 5-HT; 5-hydroxytryptamine; ELISA; LC; MHPG; MT; NA; PAG; RVM; SCS; SNI; WT; enzyme-linked immunosorbent assay; locus coeruleus; motor threshold; noradrenaline; periaqueductal gray; rostroventromedial medulla; spared nerve injury model; spinal cord stimulation; withdrawal thresholds