title: Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis.
abstract: We previously showed that peripheral noxious input after spinal cord injury (SCI) inhibits beneficial spinal plasticity and impairs recovery of locomotor and bladder functions. These observations suggest that noxious input may similarly affect the development and maintenance of chronic neuropathic pain, an important consequence of SCI. In adult rats with a moderate contusion SCI, we investigated the effect of noxious tail stimulation, administered 1 day after SCI on mechanical withdrawal responses to von Frey stimuli from 1 to 28 days after treatment. In addition, because the proinflammatory cytokine tumor necrosis factor alpha (TNFα) is implicated in numerous injury-induced processes including pain hypersensitivity, we assessed the temporal and spatial expression of TNFα, TNF receptors, and several downstream signaling targets after stimulation. Our results showed that unlike sham surgery or SCI only, nociceptive stimulation after SCI induced mechanical sensitivity by 24h. These behavioral changes were accompanied by increased expression of TNFα. Cellular assessments of downstream targets of TNFα revealed that nociceptive stimulation increased the expression of caspase 8 and the active subunit (12 kDa) of caspase 3, indicative of active apoptosis at a time point consistent with the onset of mechanical allodynia. In addition, immunohistochemical analysis revealed distinct morphological signs of apoptosis in neurons and microglia at 24h after stimulation. Interestingly, expression of the inflammatory mediator NFκB was unaltered by nociceptive stimulation. These results suggest that noxious input caudal to the level of SCI can increase the onset and expression of behavioral responses indicative of pain, potentially involving TNFα signaling.
authors.affiliation: Department of Psychology, Texas A&M University, College Station, TX 77843, USA. Electronic address: smgarraway@emory.edu.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Garraway
authors.affiliation: Department of Psychology, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Woller
authors.affiliation: Department of Neurological Surgery, Brain and Spinal Injury Center (BASIC), University of California, San Francisco, 1001 Potrero Ave, Bldg 1, Room 101, San Francisco, CA 94110, USA.
authors.forename: J Russell
authors.initials: JR
authors.lastname: Huie
authors.affiliation: Department of Psychology, Texas A&M University, College Station, TX 77843, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Hartman
authors.affiliation: Department of Psychology, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Hook
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, College of Medicine, Medical Research and Education Bldg, 8447 State Highway 47, Bryan, TX 77807-3260, USA.
authors.forename: Rajesh C
authors.initials: RC
authors.lastname: Miranda
authors.affiliation: Department of Psychology, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Yung-Jen
authors.initials: YJ
authors.lastname: Huang
authors.affiliation: Department of Neurological Surgery, Brain and Spinal Injury Center (BASIC), University of California, San Francisco, 1001 Potrero Ave, Bldg 1, Room 101, San Francisco, CA 94110, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Ferguson
authors.affiliation: Department of Psychology, Texas A&M University, College Station, TX 77843, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Grau
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology*; D006930:Hyperalgesia / Q000209:etiology*; D008124:Locomotion / Q000502:physiology; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013119:Spinal Cord Injuries / Q000150:complications*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3
keywords: Apoptosis; Mechanical allodynia; Nociceptive stimulation; Pain; Spinal cord injury; TNFα