Faculty Collaboration Database

Loss of calcineurin in the spinal dorsal horn contributes to neuropathic pain, and intrathecal administration of the phosphatase provides prolonged analgesia. Pain 2013 Oct;154(10):2024-2033

Date

06/20/2013

Pubmed ID

23778296

Pubmed Central ID

PMC3778136

DOI

10.1016/j.pain.2013.06.019

Scopus ID

2-s2.0-84884287273 (requires institutional sign-in at Scopus site)   12 Citations

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.

Author List

Miletic G, Lippitt JA, Sullivan KM, Miletic V

Author

Jennifer A. Zaspel MD Associate Professor in the Psychiatry and Behavioral Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Analgesia
Animals
Calcineurin
Injections, Spinal
Male
Neuralgia
Pain Management
Posterior Horn Cells
Random Allocation
Rats
Rats, Sprague-Dawley