Changes in Serotonin, Serotonin Transporter Expression and Serotonin Denervation Supersensitivity: Involvement in Chronic Central Pain after Spinal Hemisection in the Rat

• Published in: Experimental neurology Vol. 175; no. 2; pp. 347 - 362
• Main Authors: Hains, Bryan C., Everhart, Alex W., Fullwood, Steven D., Hulsebosch, Claire E.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01-06-2002; Elsevier
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Carrier Proteins - analysis; Carrier Proteins - metabolism; Denervation; denervation supersensitivity; Enzyme-Linked Immunosorbent Assay; Fluvoxamine - pharmacology; Hot Temperature; Hyperalgesia - drug therapy; Hyperalgesia - etiology; Hyperalgesia - metabolism; Immunohistochemistry; Injections, Spinal; Injuries of the nervous system and the skull. Diseases due to physical agents; Male; Medical sciences; Membrane Glycoproteins - analysis; Membrane Glycoproteins - metabolism; Membrane Transport Proteins; Methysergide - pharmacology; Motor Activity - drug effects; Nerve Tissue Proteins; pain; Pain - drug therapy; Pain - etiology; Pain - metabolism; Physical Stimulation; Rats; Rats, Sprague-Dawley; serotonin; Serotonin - analysis; Serotonin - metabolism; Serotonin Antagonists - pharmacology; Serotonin Plasma Membrane Transport Proteins; Serotonin Uptake Inhibitors - pharmacology; Spinal Cord - metabolism; Spinal Cord Injuries - complications; Spinal Cord Injuries - metabolism; spinal cord injury; transporter; Traumas. Diseases due to physical agents; spinal cord injury; serotonin; pain; denervation supersensitivity; transporter; Immunohistochemistry; Hindlimb; Spinal cord; Rat; Serotonine receptor; Reuptake inhibitor; Hyperalgesia; Pain; Allodynia; Human; Nervous system diseases; Serotonin; Serotonin antagonist; Rodentia; Ergot derivatives; Section; Trauma; Pathology; Vertebrata; Mammalia; Animal; Central nervous system disease; Unilateral; Spinal cord disease; Fluvoxamine; Methysergide; Denervation
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.2002.7892

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-HTT in cervical (C8) and lumbar (L5) enlargements after T13 spinal hemisection and studied the effects of intrathecally delivered 5-HT (10, 21, and 63 μg), 5-HT antagonist methysergide (125 μg/kg), and 5-HT reuptake inhibitor fluvoxamine (75 μg/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-HTT levels were not significantly changed, but at L5 there was significant ipsilateral up-regulation of 5-HTT 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-HTT 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.