Targeting Trafficking of Voltage Gated Calcium Channels: A Novel Approach in the Treatment of Pain
Vanderah, Todd W.
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PublisherThe University of Arizona.
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AbstractPain is the most common and debilitating medical problem for which patients seek medical care. Opioids remain the gold standard in the treatment of pain but are limited by poor side effect profiles such as emesis, constipation, dependence/addiction and respiratory depression. Despite a myriad of analgesic compounds on the market, tri-cyclic antidepressants, opioids, anticonvulsants, non-steroidal anti-inflammatory agents and combinations thereof, nearly two thirds of the chronic pain patients report inadequate pain relief; therefore, a new approach in the development of pain management is necessary. In recent years, the N-Type voltage gated calcium channel (CaV2.2) has become an attractive target in the treatment of chronic pain. Ziconotide, a selective CaV2.2 blocker, has been FDA approved in the United States for the treatment of severe chronic pain that is refractory to other treatments, but due to its profound side effect profile (nausea/vomiting, somnolence, vertigo, muscle spasms, myalgia, insomnia, anxiety, tremor, memory impairment and induced psychiatric disorders), the use of Ziconotide is severely limited. Mapping of the CaV2.2 interactome led to the identification of novel regulatory proteins, including collapsin response mediator protein 2 (CRMP2). Initially identified as an intracellular protein in the specification of axon/dendrite fate and axonal outgrowth, it is now known that this protein can regulate the activity of CaV2.2 and hence may be a critical regulatory node in pain modulation. Here, I describe a novel peptide aptamer derived from CRMP2, designated CaV2.2 binding domain 3 (CBD3), which when fused with the HIV transactivator of transcription protein (TAT), created tat-CBD3, which was able to significantly reverse thermal and mechanical hypersensitivity induced by the surgical incision on the plantar surface of the left hind paw in rats, a pre-clinical model of post-operative pain. Additionally, tat-CBD3 significantly attenuated thermal hypersensitivity induced via intraplantar injection of carrageenan, a model of acute inflammatory pain. Furthermore, the administration of tat-CBD3 did not produce any rewarding behaviors as measured by the conditioned placed preference (CPP) paradigm, nor did the administration of tat-CBD3 produced any motor coordination deficits measured using the rotarod performance test. Moreover, the addition of a 14-carbon myristate (myr) group to the parent peptide, myr-tat-CBD3, had increased efficacy in the attenuation of paw incision and carrageenan induced thermal/mechanical hypersensitivities when compared to the parent peptide (tat-CBD3). These types of novel compounds that lack unwanted side effects and addiction propensities are urgently needed to relieve individuals suffering from chronic pain.
Degree ProgramGraduate College