Disruption of nNOS-NOS1AP protein-protein interactions suppresses neuropathic pain in mice

Wan Hung Lee, Li Li Li, Aarti Chawla, Andy Hudmon, Yvonne Y. Lai, Michael J. Courtney, Andrea G. Hohmann

Research output: Contribution to journalArticle

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Abstract

Elevated N-methyl-D-aspartate receptor (NMDAR) activity is linked to central sensitization and chronic pain. However, NMDAR antagonists display limited therapeutic potential because of their adverse side effects. Novel approaches targeting the NR2B-PSD95-nNOS complex to disrupt signaling pathways downstream of NMDARs show efficacy in preclinical pain models. Here, we evaluated the involvement of interactions between neuronal nitric oxide synthase (nNOS) and the nitric oxide synthase 1 adaptor protein (NOS1AP) in pronociceptive signaling and neuropathic pain. TAT-GESV, a peptide inhibitor of the nNOS-NOS1AP complex, disrupted the in vitro binding between nNOS and its downstream protein partner NOS1AP but not its upstream protein partner postsynaptic density 95 kDa (PSD95). Putative inactive peptides (TAT-cp4GESV and TAT-GESVΔ1) failed to do so. Only the active peptide protected primary cortical neurons from glutamate/glycine-induced excitotoxicity. TAT-GESV, administered intrathecally (i.t.), suppressed mechanical and cold allodynia induced by either the chemotherapeutic agent paclitaxel or a traumatic nerve injury induced by partial sciatic nerve ligation. TAT-GESV also blocked the paclitaxel-induced phosphorylation at Ser15 of p53, a substrate of p38 MAPK. Finally, TAT-GESV (i.t.) did not induce NMDAR-mediated motor ataxia in the rotarod test and did not alter basal nociceptive thresholds in the radiant heat tail-flick test. These observations support the hypothesis that antiallodynic efficacy of an nNOS-NOS1AP disruptor may result, at least in part, from blockade of p38 MAPK-mediated downstream effects. Our studies demonstrate, for the first time, that disrupting nNOS-NOS1AP protein-protein interactions attenuates mechanistically distinct forms of neuropathic pain without unwanted motor ataxic effects of NMDAR antagonists.

Original languageEnglish (US)
Pages (from-to)849-863
Number of pages15
JournalPain
Volume159
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Nitric Oxide Synthase Type I
Neuralgia
Nitric Oxide Synthase
N-Methyl-D-Aspartate Receptors
Proteins
p38 Mitogen-Activated Protein Kinases
Paclitaxel
Peptides
Adaptor Protein Complex 1
Rotarod Performance Test
Central Nervous System Sensitization
Post-Synaptic Density
Hyperalgesia
Sciatic Nerve
Ataxia
Chronic Pain
Glycine
Ligation
Tail
Glutamic Acid

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Lee, W. H., Li, L. L., Chawla, A., Hudmon, A., Lai, Y. Y., Courtney, M. J., & Hohmann, A. G. (2018). Disruption of nNOS-NOS1AP protein-protein interactions suppresses neuropathic pain in mice. Pain, 159(5), 849-863. https://doi.org/10.1097/j.pain.0000000000001152

Disruption of nNOS-NOS1AP protein-protein interactions suppresses neuropathic pain in mice. / Lee, Wan Hung; Li, Li Li; Chawla, Aarti; Hudmon, Andy; Lai, Yvonne Y.; Courtney, Michael J.; Hohmann, Andrea G.

In: Pain, Vol. 159, No. 5, 01.05.2018, p. 849-863.

Research output: Contribution to journalArticle

Lee, WH, Li, LL, Chawla, A, Hudmon, A, Lai, YY, Courtney, MJ & Hohmann, AG 2018, 'Disruption of nNOS-NOS1AP protein-protein interactions suppresses neuropathic pain in mice', Pain, vol. 159, no. 5, pp. 849-863. https://doi.org/10.1097/j.pain.0000000000001152
Lee, Wan Hung ; Li, Li Li ; Chawla, Aarti ; Hudmon, Andy ; Lai, Yvonne Y. ; Courtney, Michael J. ; Hohmann, Andrea G. / Disruption of nNOS-NOS1AP protein-protein interactions suppresses neuropathic pain in mice. In: Pain. 2018 ; Vol. 159, No. 5. pp. 849-863.
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