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Gene Therapy for Chronic Pain: How to Manipulate and Unravel Pain Control Circuits from the Brain?

  • Isabel Martins
  • Isaura TavaresEmail author
Protocol
Part of the Neuromethods book series (NM, volume 98)

Abstract

The increasing prevalence of chronic pain imposes to search for new therapeutic approaches. Despite the increase in basic and clinical pain research during the last decades, the available analgesic drugs remained considerably unchanged. Gene therapy emerged as an important tool in the pain field. Studies in experimental pain models consisted on blockade of nociceptive transmission at the spinal cord by peripheral delivery of viral vectors (mainly replication-defective forms of herpes simplex virus type 1, HSV-1). Based on these results, clinical trials using gene therapy were successfully implemented in cancer patients with intractable pain.

The studies at the spinal cord opened the possibility to use gene transfer to interfere in a specific and sustained manner with pain control areas of the brain. Our research group departed from detailed morphological and functional characterization of pain control circuits of the brainstem to develop strategies to manipulate those areas using HSV-1 vectors. First, we established the dynamics of migration of HSV-1 upon injection into a unique pain facilitatory area of the medulla oblongata (the dorsal reticular nucleus-DRt). At shorter postinjection timepoints, transduction occurred mainly at the DRt, whereas at longer times a selective migration was detected in DRt brain afferents. Since some of those afferents were noradrenergic and based on the role of noradrenaline in increasing pain facilitation from the DRt, we engineered an HSV-1 vector that contains the tyrosine hydroxylase (TH) promoter and the TH transgene in antisense orientation. This vector decreased neuropathic pain behaviors for about a month. Similar studies addressing other brain areas involved in descending pain modulation are necessary to fully ascertain the full potential of gene therapy for chronic pain control.

Key words

HSV-1 Descending pain modulation Noradrenaline Analgesia 

Abbreviations

β-Gal

β-Galactosidase

DRG

Dorsal root ganglion

DRt

Dorsal reticular nucleus

GABA

γ-Aminobutyric acid

GAD

Glutamate decarboxylase

HCMV

Human cytomegalovirus

HSV-1

Herpes simplex virus type 1

TH

Tyrosine hydroxylase

Notes

Acknowledgments

The current research was supported by FCT Project PTDC/SAU-NSC/110954/2009 and FCOMP-01-0124-FEDER-015900.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Experimental Biology, Faculty of Medicine of PortoUniversity of PortoPortoPortugal
  2. 2.Instituto de Biologia Molecular e CelularUniversity of PortoPortoPortugal

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