title: Loss of calcineurin in the spinal dorsal horn contributes to neuropathic pain, and intrathecal administration of the phosphatase provides prolonged analgesia.
abstract: Calcineurin (protein phosphatase 3) regulates synaptic plasticity in the brain. The development of neuropathic pain appears dependent on some of the same mechanisms that underlie brain synaptic plasticity. In this study, we examined whether calcineurin regulates chronic constriction injury (CCI)-elicited plasticity in the spinal dorsal horn. CCI animals exhibited mechanical and thermal hypersensitivity 7 days after ligation of the sciatic nerve. Neither control uninjured nor sham-operated animals exhibited pain behavior. Calcineurin activity and content of its Aα isoform were significantly decreased in the ipsilateral postsynaptic density (PSD) of dorsal horn neurons in CCI animals. Calcineurin activity and content in the contralateral PSD of CCI animals or either side of the dorsal horn in sham animals were not modified. The pain behavior in CCI animals was attenuated by intrathecal application of exogenous calcineurin. The treatment was long-lasting as a single injection provided analgesia for 4 days by restoring the phosphatase's activity and Aα content in the PSD. No signs of toxicity were detected up to 14 days after the single intrathecal injection. Intrathecal application of the calcineurin inhibitor FK-506 elicited pain behavior in control uninjured animals and significantly reduced calcineurin activity in the PSD. CCI may elicit neuropathic pain at least in part as a result of the loss of calcineurin-mediated dephosphorylation in the dorsal horn. Addition of the phosphatase by intrathecal injection reverses the injury-elicited loss and provides prolonged pain relief. Clinical therapy with calcineurin may prove to be a novel, effective, and safe approach in the management of well-established neuropathic pain.
authors.affiliation: Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
authors.forename: Gordana
authors.initials: G
authors.lastname: Miletic
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lippitt
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Sullivan
authors.forename: Vjekoslav
authors.initials: V
authors.lastname: Miletic
mesh_terms: D000698:Analgesia / Q000379:methods*; D000818:Animals; D019703:Calcineurin / Q000008:administration & dosage* / Q000096:biosynthesis*; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D059408:Pain Management / Q000379:methods; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019703:Calcineurin
keywords: Central sensitization; Chronic constriction injury; Neuropathic pain; Nociception; Phosphatase; Postsynaptic density; Rat; Spinal dorsal horn; Synaptic plasticity