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

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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Overexpression of µ-Opioid Receptors in Peripheral Afferents, but Not in Combination with Enkephalin, Decreases Neuropathic Pain Behavior and Enhances Opioid Analgesia in Mouse

Anesthesiology ◽

10.1097/aln.0000000000002063 ◽

2018 ◽

Vol 128 (5) ◽

pp. 967-983 ◽

Cited By ~ 11

Author(s):

Amanda H. Klein ◽

Husam K. Mohammad ◽

Rabiah Ali ◽

Brad Peper ◽

Steven P. Wilson ◽

...

Keyword(s):

Neuropathic Pain ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Opioid Receptor ◽

Opioid Receptors ◽

Herpes Simplex Virus Type ◽

Viral Vector ◽

Control Group ◽

Opioid Analgesia ◽

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

Molecular Therapy ◽

10.1016/s1525-0016(16)37322-1 ◽

2011 ◽

Vol 19 ◽

pp. S286-S287

Keyword(s):

Neuropathic Pain ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Opioid Receptor ◽

Primary Afferents ◽

Pain Modulation ◽

Receptor Expression ◽

Delta Opioid Receptor ◽

Simplex Virus

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Renaturation of complementary DNA strands by herpes simplex virus type 1 ICP8.

Journal of Virology ◽

10.1128/jvi.67.12.6945-6949.1993 ◽

1993 ◽

Vol 67 (12) ◽

pp. 6945-6949 ◽

Cited By ~ 36

Author(s):

R E Dutch ◽

I R Lehman

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Complementary Dna ◽

Dna Strands ◽

Simplex Virus

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Synthesis and Evaluation of Some Uracil Nucleosides as Promising Anti-Herpes Simplex Virus 1 Agents

Molecules ◽

10.3390/molecules26102988 ◽

2021 ◽

Vol 26 (10) ◽

pp. 2988

Author(s):

Samir Mohamed Awad ◽

Shima Mahmoud Ali ◽

Yara Essam Mansour ◽

Samar Said Fatahala

Keyword(s):

Drug Resistance ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Side Effects ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Herpes Simplex Virus 1 ◽

Simplex Virus ◽

Hsv 1

Since herpes simplex virus type 1 (HSV-1) infection is so widespread, several antiviral drugs have been developed to treat it, among which are uracil nucleosides. However, there are major problems with the current medications such as severe side-effects and drug resistance. Here we present some newly synthesized cyclic and acyclic uracil nucleosides that showed very promising activity against HSV-1 compared to acyclovir.

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Assembly of VP26 in herpes simplex virus-1 capsid implicated by 3-D structure of recombinant capsid

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100140579 ◽

1995 ◽

Vol 53 ◽

pp. 840-841

Author(s):

Z. Hong Zhou ◽

Jing He ◽

Joanita Jakana ◽

J. D. Tatman ◽

Frazer J. Rixon ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

3D Structure ◽

Structure Study ◽

Herpes Simplex Virus 1 ◽

Shell Proteins ◽

Life Threatening ◽

Infected Cells ◽

Simplex Virus ◽

Hsv 1

Herpes simplex virus-1 (HSV-1) is a ubiquitous virus which is implicated in diseases ranging from self-curing cold sores to life-threatening infections. The 2500 Å diameter herpes virion is composed of a glycoprotein spike containing, lipid envelope, enclosing a protein layer (the tegument) in which is embedded the capsid (which contains the dsDNA genome). The B-, and A- and C-capsids, representing different morphogenetic stages in HSV-1 infected cells, are composed of 7, and 5 structural proteins respectively. The three capsid types are organized in similar T=16 icosahedral shells with 12 pentons, 150 hexons, and 320 connecting triplexes. Our previous 3D structure study at 26 Å revealed domain features of all these structural components and suggested probable locations for the outer shell proteins, VP5, VP26, VP19c and VP23. VP5 makes up most of both pentons and hexons. VP26 appeared to bind to the VP5 subunit in hexon but not to that in penton.

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Application of EM to differentiate herpes virus from pox virus in genital specimens

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100169043 ◽

1994 ◽

Vol 52 ◽

pp. 262-263

Author(s):

K. Rekrut ◽

K. Schleuter

Keyword(s):

Tissue Culture ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Fresh Tissue ◽

Culture Cells ◽

Viral Transport ◽

Carbon Coated ◽

Immuno Assay ◽

Simplex Virus ◽

Enzyme Immuno Assay

Confirmation of herpes simplex virus (HSV) from genital lesions of obstetrical (OB) patients may affect both the management of the delivery and of the neonate.(l,2) During 1992 and 1993, 4,450 genital specimens from OB patients were submitted in viral transport media for herpes culture. The specimens were inoculated into MRC-5, Vero, and A-549 tissue culture tubes, incubated, and examined daily for 7 days for cytopathic effect (CPE). The original specimens were frozen at −70° C until final reports were issued. Culture tubes with CPE were tested by the Dupont Herpchek enzyme immuno assay (EIA) to confirm the presence of herpes simplex virus (HSV). (3,4) 170 OB patient specimens were positive by culture and confirmed by EIA.There were also 63 cultures exhibiting CPE ressembling HSV which were negative by EIA testing, which failed to pass in fresh tissue culture cells or progress to more enhanced CPE in culture. These original specimens were screened by electron microscopy after direct ultracentrifugation employing the Beckman airfuge with the EM 90 rotor on to formvar carbon-coated 300 mesh copper grids and negatively stained with 2% PTA.

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