Targeting Trafficking of Voltage Gated Calcium Channels: A Novel Approach in the Treatment of Pain

Persistent Link:
http://hdl.handle.net/10150/556952
Title:
Targeting Trafficking of Voltage Gated Calcium Channels: A Novel Approach in the Treatment of Pain
Author:
Wang, Yue
Issue Date:
2015
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Pain 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.
Type:
text; Electronic Thesis
Keywords:
CRMP2; Pain; Medical Pharmacology; Calcium Channels
Degree Name:
M.S.
Degree Level:
masters
Degree Program:
Graduate College; Medical Pharmacology
Degree Grantor:
University of Arizona
Advisor:
Khanna, Rajesh; Vanderah, Todd W.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleTargeting Trafficking of Voltage Gated Calcium Channels: A Novel Approach in the Treatment of Painen_US
dc.creatorWang, Yueen
dc.contributor.authorWang, Yueen
dc.date.issued2015en
dc.publisherThe University of Arizona.en
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en
dc.description.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.en
dc.typetexten
dc.typeElectronic Thesisen
dc.subjectCRMP2en
dc.subjectPainen
dc.subjectMedical Pharmacologyen
dc.subjectCalcium Channelsen
thesis.degree.nameM.S.en
thesis.degree.levelmastersen
thesis.degree.disciplineGraduate Collegeen
thesis.degree.disciplineMedical Pharmacologyen
thesis.degree.grantorUniversity of Arizonaen
dc.contributor.advisorKhanna, Rajeshen
dc.contributor.advisorVanderah, Todd W.en
dc.contributor.committeememberKhanna, Rajeshen
dc.contributor.committeememberVanderah, Todd W.en
dc.contributor.committeememberLargent-Milnes, Tally M.en
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