Enhanced Peripheral Analgesia Using Virally Mediated Gene Transfer of the μ-Opioid Receptor in Mice

Zhang, Guohua; Mohammad, Husam K.; Peper, Brad; Raja, Srinivasa N.; Wilson, Steven P.; Sweitzer, Sarah M.

doi:10.1097/01.anes.0000299836.61785.79

Cited by 20 publications

(31 citation statements)

References 51 publications

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“…The following viral vectors have been described 36 : hsvCON, the control virus expresses β-galactosidase ( E. coli lacZ) that is driven by the CMV immediate-early enhancer promoter, previously called SGZ, cmvMOR expresses MOR and is driven by the CMV immediate-early enhancer promoter, previously called SGMOR. A newly constructed virus, galMOR expresses MOR under the control of the galanin promoter (Fig.…”

Section: Methodsmentioning

confidence: 99%

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Injury-Specific Promoters Enhance Herpes Simplex Virus–Mediated Gene Therapy for Treating Neuropathic Pain in Rodents

Smith

Paige

Velázquez

et al. 2015

The Journal of Pain

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Chronic neuropathic pain is often difficult to treat with current pain medications. Gene therapy is currently being explored as a therapeutic approach for the treatment of neuropathic and cancer pain. In this study we sought to use an injury-specific promoter to deliver the mu opioid receptor (MOR) transgene such that expression would only occur during the injured state in response to release of injury-specific galanin. To determine whether an injury specific promoter can produce neuron-specific MOR expression and enhanced antinociception we compared animals infected with a galanin promoter virus (galMOR) or a human cytomegalovirus (CMV) promoter virus. (cmvMOR). In behavioral assays, we found an earlier onset and a larger magnitude of antinociception in animals infected with galMOR compared to cmvMOR. Immunohistochemistry of dorsal root ganglion (DRG) neurons revealed a significant increase in MOR positive staining in cmvMOR and galMOR treated mice. Spinal cord sections from galMOR treated mice showed a greater increase in density but not area of MOR positive staining. These results suggest that using injury-specific promoters to drive gene expression in primary afferent neurons can influence the onset and magnitude of antinociception in a rodent model of neuropathic pain and can be used to upregulate MOR expression in populations of neurons that are potentially injury specific. Perspective An injury specific promoter (galMOR) was used to drive MOR expression in a population- and injury- specific manner. GalMOR increased antinociception and density of MOR staining in spinal cord. This article presents evidence that promoter selection is an important component in successful gene expression in an injury- and population-specific manner.

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Section: Methodsmentioning

confidence: 99%

“…Immunohistochemistry was performed as previously reported 36 . Briefly, 2 weeks after virus infection, mice were deeply anesthetized with isoflurane then transcardially perfused with 0.1M phosphate buffered saline (PBS) followed by 4% paraformaldehyde in 0.1 M PBS.…”

Section: Methodsmentioning

confidence: 99%

Injury-Specific Promoters Enhance Herpes Simplex Virus–Mediated Gene Therapy for Treating Neuropathic Pain in Rodents

Smith

Paige

Velázquez

et al. 2015

The Journal of Pain

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“…Recombinant herpes viruses were constructed as previously described [66]. The pre-miRNA sequences against mouse ASIC3, miR844, and the control miRNA were excised from their respective plasmids (pcDNA6.2-GW EmGFP-miR) along with the EmGFP sequence, and inserted downstream of the human cytomegalovirus (CMV) immediate-early enhancer–promoter in a shuttle plasmid containing portions of the HSV-1 genes UL36 and UL37 flanking the expression cassette.…”

Section: Methodsmentioning

confidence: 99%

“…The expression cassette also contained the woodchuck hepatitis virus element to enhance RNA stability. The resultant HSV are more selective for infecting the peripheral nervous system [66]. The cloned pre-miRNA sequences were verified by DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

Selective targeting of ASIC3 using artificial miRNAs inhibits primary and secondary hyperalgesia after muscle inflammation

Walder

Gautam

Wilson

et al. 2011

Pain

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Acid-sensing ion channels (ASICs) are activated by acidic pH and may play a significant role in the development of hyperalgesia. Earlier studies show ASIC3 is important for induction of hyperalgesia after muscle insult using ASIC3−/− mice. ASIC3−/− mice lack ASIC3 throughout the body, and the distribution and composition of ASICs could be different from wild-type mice. We therefore tested whether knockdown of ASIC3 in primary afferents innervating muscle of adult wild-type mice prevented development of hyper-algesia to muscle inflammation. We cloned and characterized artificial miRNAs (miR-ASIC3) directed against mouse ASIC3 (mASIC3) to downregulate ASIC3 expression in vitro and in vivo. In CHO-K1 cells transfected with mASIC3 cDNA in culture, the miR-ASIC3 constructs inhibited protein expression of mASIC3 and acidic pH-evoked currents and had no effect on protein expression or acidic pH-evoked currents of ASIC1a. When miR-ASIC3 was used in vivo, delivered into the muscle of mice using a herpes simplex viral vector, both muscle and paw mechanical hyperalgesia were reduced after carrageenan-induced muscle inflammation. ASIC3 mRNA in DRG and protein levels in muscle were decreased in vivo by miRASIC3. In CHO-K1 cells co-transfected with ASIC1a and ASIC3, miR-ASIC3 reduced the amplitude of acidic pH-evoked currents, suggesting an overall inhibition in the surface expression of heteromeric ASIC3-containing channels. Our results show, for the first time, that reducing ASIC3 in vivo in primary afferent fibers innervating muscle prevents the development of inflammatory hyperalgesia in wild-type mice, and thus, may have applications in the treatment of musculoskeletal pain in humans.

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“…Using a green fluorescent protein reporter gene, we demonstrated that the HSV vectors were incorporated into small and large cells in the DRG. 55 Administration of the SGMOR virus led to an increase in expression of mORs, which were transported from the DRG both anterograde to central spinal terminals and retrograde to the skin afferent endings in the periphery (Fig. 1).…”

Section: Enhancing Peripheral Opioid Receptorsvvirus-mediated Gene Trmentioning

confidence: 99%

Modulating Pain in the Periphery

Raja

2012

Regional Anesthesia and Pain Medicine

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This article provides a brief overview of earlier work of our group on the peripheral signaling of pain, summarizes more recent studies on the role of opioids in chronic neuropathic pain, and speculates on the future of gene-based therapies as novel strategies to enhance the peripheral modulation of pain. Neurophysiological and psychophysical studies have revealed features of primary afferent activity from somatic tissue that led to improved understanding of the physiology and pathophysiology of pain signaling by nociceptive and non-nociceptive fibers. The demonstration of peripheral opioid mechanisms in neuropathic pain suggests a potential role for these receptors in the modulation of pain at its initiation site. Our work has focused on characterizing this peripheral opioid analgesia in chronic neuropathic pain such that it can be exploited to develop novel and potent peripheral analgesics for its treatment. Ongoing research on virus-mediated gene transfer strategies to enhance peripheral opioid analgesia is presented.

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Enhanced Peripheral Analgesia Using Virally Mediated Gene Transfer of the μ-Opioid Receptor in Mice

Abstract: This gene therapy approach may provide an innovative strategy to enhance peripheral opioid analgesia for the treatment of pain in humans, thereby minimizing centrally mediated opioid side effects such as sedation and addiction.

Cited by 20 publications

References 51 publications

Injury-Specific Promoters Enhance Herpes Simplex Virus–Mediated Gene Therapy for Treating Neuropathic Pain in Rodents

Injury-Specific Promoters Enhance Herpes Simplex Virus–Mediated Gene Therapy for Treating Neuropathic Pain in Rodents

Selective targeting of ASIC3 using artificial miRNAs inhibits primary and secondary hyperalgesia after muscle inflammation

Modulating Pain in the Periphery

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