Damiana Scuteri1, Laura Rombolà2, Silvia Natoli3, Antonio Pisani4,5, Paola Bonsi5, Chizuko Watanabe6, Giacinto Bagetta1, Paolo Tonin7, Maria Tiziana Corasaniti8. 1. Pharmacotechnology Documentation and Transfer Unit, Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy. 2. Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy. 3. Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy. 4. Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy. 5. IRCCS Fondazione Santa Lucia, 00179 Rome, Italy. 6. Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai 981-8558, Japan. 7. Regional Center for Serious Brain Injuries, S. Anna Institute, 88900 Crotone, Italy. 8. School of Hospital Pharmacy, University "Magna Graecia" of Catanzaro and Department of Health Sciences, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
Abstract
BACKGROUND: DYT1 dystonia is the most common form of early-onset inherited dystonia, which is caused by mutation of torsin A (TA) belonging to the "ATPases associated with a variety of cellular activities" (AAA + ATPase). Dystonia is often accompanied by pain, and neuropathic pain can be associated to peripherally induced movement disorder and dystonia. However, no evidence exists on the effect of gabapentin in mice subjected to neuropathic pain model overexpressing human normal or mutated TA. METHODS: Mice subjected to L5 spinal nerve ligation (SNL) develop mechanical allodynia and upregulation of the α2δ-1 L-type calcium channel subunit, forming a validated experimental model of neuropathic pain. Under these experimental conditions, TA is expressed in dorsal horn neurons and astrocytes and colocalizes with α2δ-1. Similar to this subunit, TA is overexpressed in dorsal horn 7 days after SNL. This model has been used to investigate (1) basal mechanical sensitivity; (2) neuropathic pain phases; and (3) the effect of gabapentin, an α2δ-1 ligand used against neuropathic pain, in non-transgenic (NT) C57BL/6 mice and in mice overexpressing human wild-type (hWT) or mutant (hMT) TA. RESULTS: In comparison to non-transgenic mice, the threshold for mechanical sensitivity in hWT or hMT does not differ (Kruskal-Wallis test = 1.478; p = 0.4777, although, in the latter animals, neuropathic pain recovery phase is delayed. Interestingly, gabapentin (100 mg/Kg) reduces allodynia at its peak (occurring between post-operative day 7 and day 10) but not in the phase of recovery. CONCLUSIONS: These data lend support to the investigation on the role of TA in the molecular machinery engaged during neuropathic pain.
BACKGROUND:DYT1 dystonia is the most common form of early-onset inherited dystonia, which is caused by mutation of torsin A (TA) belonging to the "ATPases associated with a variety of cellular activities" (AAA + ATPase). Dystonia is often accompanied by pain, and neuropathic pain can be associated to peripherally induced movement disorder and dystonia. However, no evidence exists on the effect of gabapentin in mice subjected to neuropathic pain model overexpressing human normal or mutated TA. METHODS:Mice subjected to L5 spinal nerve ligation (SNL) develop mechanical allodynia and upregulation of the α2δ-1 L-type calcium channel subunit, forming a validated experimental model of neuropathic pain. Under these experimental conditions, TA is expressed in dorsal horn neurons and astrocytes and colocalizes with α2δ-1. Similar to this subunit, TA is overexpressed in dorsal horn 7 days after SNL. This model has been used to investigate (1) basal mechanical sensitivity; (2) neuropathic pain phases; and (3) the effect of gabapentin, an α2δ-1 ligand used against neuropathic pain, in non-transgenic (NT) C57BL/6 mice and in mice overexpressing human wild-type (hWT) or mutant (hMT) TA. RESULTS: In comparison to non-transgenic mice, the threshold for mechanical sensitivity in hWT or hMT does not differ (Kruskal-Wallis test = 1.478; p = 0.4777, although, in the latter animals, neuropathic pain recovery phase is delayed. Interestingly, gabapentin (100 mg/Kg) reduces allodynia at its peak (occurring between post-operative day 7 and day 10) but not in the phase of recovery. CONCLUSIONS: These data lend support to the investigation on the role of TA in the molecular machinery engaged during neuropathic pain.
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