Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential
| Autor: | Frank Porreca, Matthew S. Ripsch, Yue Wang, Chaoling Qu, Yuying Wang, Lauren M. Federici, May Khanna, Todd W. Vanderah, Stephanie D. Fitz, Xiaofang Yang, Jennifer Y. Xie, Fletcher A. White, Rajesh Khanna, Aubin Moutal, Philip L. Johnson, Lindsey A. Chew, Michael R. Due |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pain Threshold Sensory Receptor Cells Dopamine Action Potentials Nerve Tissue Proteins Pharmacology Nucleus accumbens Anxiety Nucleus Accumbens Article Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Dorsal root ganglion Ganglia Spinal Threshold of pain medicine Animals Maze Learning Electric Stimulation Rats Mice Inbred C57BL Disease Models Animal 030104 developmental biology Anesthesiology and Pain Medicine medicine.anatomical_structure Allodynia Nociception Neurology Hindlimb Suspension Hyperalgesia Neuropathic pain Exploratory Behavior Intercellular Signaling Peptides and Proteins Neuralgia Female Neurology (clinical) medicine.symptom Psychology Neuroscience 030217 neurology & neurosurgery Aptamers Peptide medicine.drug |
| Zdroj: | Pain. 157(9) |
| ISSN: | 1872-6623 |
| Popis: | Uncoupling the protein-protein interaction between collapsin response mediator protein 2 (CRMP2) and N-type voltage-gated calcium channel (CaV2.2) with an allosteric CRMP2-derived peptide (CBD3) is antinociceptive in rodent models of inflammatory and neuropathic pain. We investigated the efficacy, duration of action, abuse potential, and neurobehavioral toxicity of an improved mutant CRMP2 peptide. A homopolyarginine (R9)-conjugated CBD3-A6K (R9-CBD3-A6K) peptide inhibited the CaV2.2-CRMP2 interaction in a concentration-dependent fashion and diminished surface expression of CaV2.2 and depolarization-evoked Ca influx in rat dorsal root ganglia neurons. In vitro studies demonstrated suppression of excitability of small-to-medium diameter dorsal root ganglion and inhibition of subtypes of voltage-gated Ca channels. Sprague-Dawley rats with tibial nerve injury had profound and long-lasting tactile allodynia and ongoing pain. Immediate administration of R9-CBD3-A6K produced enhanced dopamine release from the nucleus accumbens shell selectively in injured animals, consistent with relief of ongoing pain. R9-CBD3-A6K, when administered repeatedly into the central nervous system ventricles of naive rats, did not result in a positive conditioned place preference demonstrating a lack of abusive liability. Continuous subcutaneous infusion of R9-CBD3-A6K over a 24- to 72-hour period reversed tactile allodynia and ongoing pain, demonstrating a lack of tolerance over this time course. Importantly, continuous infusion of R9-CBD3-A6K did not affect motor activity, anxiety, depression, or memory and learning. Collectively, these results validate the potential therapeutic significance of targeting the CaV-CRMP2 axis for treatment of neuropathic pain. |
| Databáze: | OpenAIRE |
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