Changes in serotonin, serotonin transporter expression and serotonin denervation supersensitivity: involvement in chronic central pain after spinal hemisection in the rat.
Spinal cord injury (SCI) results in abnormal locomotor and pain syndromes in humans. In a rodent SCI model, T13 unilateral spinal hemisection results in bilateral mechanical allodynia and thermal hyperalgesia, partly by interruption of tonic descending serotonin (5-HT) inhibition. In the current study, we examined changes in density and distribution of 5-HT and 5-HT(T) in cervical (C8) and lumbar (L5) enlargements after T13 spinal hemisection and studied the effects of intrathecally delivered 5-HT (10, 21, and 63 microg), 5-HT antagonist methysergide (125 microg/kg), and 5-HT reuptake inhibitor fluvoxamine (75 microg/kg) on pain-related behaviors. Thirty-day-old male Sprague-Dawley rats were spinally hemisected and sacrificed at 3 (n = 20) and 28 (n = 20) days postsurgery for immunohistochemistry, Western blot, and ELISA analysis and compared against sham-operated animals (n = 10). At day 3, C8 5-HT levels were not significantly changed but at L5 there was a significant decrease in ipsilateral 5-HT in laminae I-II followed by incomplete recovery at 28 days postinjury. At both 3 and 28 days postinjury, C8 5-HT(T) levels were not significantly changed, but at L5 there was significant ipsilateral up-regulation of 5-HT(T) in laminae I-II. A second group of animals (n = 30) was hemisected and, starting at 28 days postinjury, behaviorally tested with intrathecal compounds. Increasing doses of 5-HT attenuated both fore- and hindlimb mechanical allodynia and thermal hyperalgesia, and effects of endogenous 5-HT were attenuated by methysergide and enhanced with fluvoxamine, all without locomotor alterations. Sham controls (n = 10) were unaffected. Thus, permanent changes occur in 5-HT and 5-HT(T) after SCI, denervation 5-HT supersensitivity develops, and modulation of 5-HT attenuates pain-related behaviors. Insight gained by these studies may aid in the understanding of dynamic 5-HT systems which will be useful in treating chronic central pain after SCI.
Hains
Bryan C
BC
Department of Anatomy and Neurosciences, Marine Biomedical Institute, University of Texas Medical Branch, 301 University Boulevard, Galveston 77555-1043, USA.
Everhart
Alex W
AW
Fullwood
Steven D
SD
Hulsebosch
Claire E
CE
D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D003714:Denervation; D004797:Enzyme-Linked Immunosorbent Assay; D016666:Fluvoxamine / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008784:Methysergide / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013116:Spinal Cord / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism*
D002352:Carrier Proteins; D016666:Fluvoxamine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008784:Methysergide; D009419:Nerve Tissue Proteins; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat