749. Peripheral Delta Opioid Receptor-Mediated Analgesia and Neuropathic Pain: Modulation of Receptor Expression in Primary Afferents Using Herpes Simplex Virus

Abstract Background The current study used recombinant herpes simplex virus type I to increase expression of µ-opiate receptors and the opioid ligand preproenkephalin in peripheral nerve fibers in a mouse model of neuropathic pain. It was predicted that viral vector delivery of a combination of genes encoding the µ-opioid receptor and preproenkephalin would attenuate neuropathic pain and enhance opioid analgesia. The behavioral effects would be paralleled by changes in response properties of primary afferent neurons. Methods Recombinant herpes simplex virus type 1 containing cDNA sequences of the µ-opioid receptor, human preproenkephalin, a combination, or Escherichia coli lacZ gene marker (as a control) was used to investigate the role of peripheral opioids in neuropathic pain behaviors. Results Inoculation with the µ-opioid receptor viral vector (n = 13) reversed mechanical allodynia and thermal hyperalgesia and produced leftward shifts in loperamide (ED50 = 0.6 ± 0.2 mg/kg vs. ED50 = 0.9 ± 0.2 mg/kg for control group, n = 8, means ± SD) and morphine dose-response curves (ED50 = 0.3 ± 0.5 mg/kg vs. ED50 = 1.1 ± 0.1 mg/kg for control group). In µ-opioid receptor viral vector inoculated C-fibers, heat-evoked responses (n = 12) and ongoing spontaneous activity (n = 18) were decreased after morphine application. Inoculation with both µ-opioid receptor and preproenkephalin viral vectors did not alter mechanical and thermal responses. Conclusions Increasing primary afferent expression of opioid receptors can decrease neuropathic pain-associated behaviors and increase systemic opioid analgesia through inhibition of peripheral afferent fiber activity.

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

Journal of Pain ◽

10.1016/j.jpain.2014.12.007 ◽

2015 ◽

Vol 16 (3) ◽

pp. 283-290 ◽

Cited By ~ 6

Author(s):

Sherika N. Smith ◽

Candler Paige ◽

Kandy T. Velazquez ◽

Terika P. Smith ◽

Srinivasa N. Raja ◽

...

Keyword(s):

Gene Therapy ◽

Neuropathic Pain ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Simplex Virus

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Innate Immune Responses to Herpes Simplex Virus Type 2 Influence Skin Homing Molecule Expression by Memory CD4+ Lymphocytes

Journal of Virology ◽

10.1128/jvi.80.6.2863-2872.2006 ◽

2006 ◽

Vol 80 (6) ◽

pp. 2863-2872 ◽

Cited By ~ 12

Author(s):

David M. Koelle ◽

Jay Huang ◽

Michael T. Hensel ◽

Christopher L. McClurkan

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Cd4 T Cells ◽

Receptor Expression ◽

Homing Receptor ◽

Skin Homing ◽

Simplex Virus

ABSTRACT Herpes simplex virus (HSV) infections of humans are characterized by intermittent, lytic replication in epithelia. Circulating HSV-specific CD4 T cells express lower levels of preformed cutaneous lymphocyte-associated antigen (CLA), a skin-homing receptor, than do circulating HSV-specific CD8 T cells but, paradoxically, move into infected skin earlier than CD8 cells. Memory CD4 T cells develop strong and selective expression of CLA and E-selectin ligand while responding to HSV antigen in vitro. We now show that interleukin-12, type I interferon, and transforming growth factor beta are each involved in CLA expression by memory HSV type 2 (HSV-2)-specific CD4 T cells in peripheral blood mononuclear cells (PBMC). A reduction of the number of monocytes and dendritic cells from PBMC reduces CLA expression by HSV-2-responsive CD4 lymphoblasts, while their reintroduction restores this phenotype, identifying these cells as possible sources of CLA-promoting cytokines. Plasmacytoid dendritic cells are particularly potent inducers of CLA on HSV-reactive CD4 T cells. These observations are consistent with cooperation between innate and acquired immunity to promote a pattern of homing receptor expression that is physiologically appropriate for trafficking to infected tissues.

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

Anesthesiology ◽

10.1097/01.anes.0000299836.61785.79 ◽

2008 ◽

Vol 108 (2) ◽

pp. 305-313 ◽

Cited By ~ 19

Author(s):

Guohua Zhang ◽

Husam Mohammad ◽

Brad D. Peper ◽

Srinivasa Raja ◽

Steven P. Wilson ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Side Effects ◽

Opioid Receptor ◽

Opioid Analgesia ◽

Complementary Dna ◽

Innovative Strategy ◽

Peripheral Analgesia ◽

Peripheral Opioid Analgesia ◽

Simplex Virus

Background The use of opioids to treat pain is often limited by side effects mediated through the central nervous system. The current study used a recombinant herpes simplex virus type 1 to increase expression of the mu-opioid receptor (muOR) in primary afferent neurons. The goal of this strategy was to enhance peripheral opioid analgesia. Methods Cutaneous inoculation with herpes simplex virus containing muOR complementary DNA (cDNA) in antisense (SGAMOR) or sense (SGMOR) orientation relative to a constitutive promoter, or complementary DNA for Escherichia coli lac Z gene as a control virus (SGZ) was used to modify the levels of muOR in primary afferents. The effects of altered muOR levels on peripheral analgesia were then examined. Results At 4 weeks after SGAMOR and SGMOR infection, decreased and increased muOR immunoreactivity was observed in ipsilateral dorsal hind paw skin, lumbar dorsal root ganglion cells, and superficial dorsal horns, respectively, compared with SGZ. This change in muOR expression in mice by SGAMOR and SGMOR was accompanied at the behavioral level with a rightward and leftward shift in the loperamide dose-response curve, respectively, compared with SGZ. Conclusions 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.

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