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Long-term pain relief in canine osteoarthritis by a single intra-articular injection of resiniferatoxin, a potent TRPV1 agonist

Iadarola, Michael J.a,*; Sapio, Matthew R.a; Raithel, Stephen J.a; Mannes, Andrew J.a; Brown, Dorothy Ciminob

doi: 10.1097/j.pain.0000000000001314
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The translational potential of analgesic approaches emerging from basic research can be augmented by client-owned dog trials. We report on a peripheral interventional approach that uses intra-articular injection of the ultrapotent TRPV1 agonist resiniferatoxin (RTX) to produce a selective long-term chemoinactivation of nociceptive primary afferent nerve endings for pain control in naturally occurring canine osteoarthritis. A single injection of 10 µg of RTX, produced suppression of pain, improvement in gait, weight bearing, and improvement in the dog's activities of daily living lasting 4 months or longer. Two to 3 years after the injection, there are no alterations to suggest that removal of inflammatory pain caused accelerated joint degeneration (Charcot joint) in any of the dogs. To amplify the effective use of canine subjects in translational analgesia research, we report a high-quality canine dorsal root ganglion transcriptome. Some targets for analgesia are highly conserved both in protein sequence and level of expression within a target tissue while others diverge substantially from the human. This knowledge is especially important for development of analgesics aimed at peripheral molecular targets and provides a template for informed translational research. The peripheral site of action, long duration of analgesia, apparent safety, and retention of coordination, all resulting from a single dose suggest that intra-articular RTX may be an effective intervention for osteoarthritis pain with few or no side effects and lead to an improved quality of life.

We investigate nonopioid peripheral analgesia using intra-articular resiniferatoxin in canine subjects with naturally occurring osteoarthritis and present the corresponding transcriptional fingerprint of the dog dorsal root ganglion to enable informed translational studies.

aDepartment of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States

bTranslational and Comparative Medical Research, Elanco Animal Health, Greenfield, IN, United States

Corresponding author. Address: Department of Perioperative Medicine, Clinical Center, NIH, Building 10 Room 3D56, 10 Center Dr, Bethesda, MD 20892-1510, United States. Tel.: (301)-496-2758. E-mail address: michael.iadarola@nih.gov (M.J. Iadarola).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

M.J. Iadarola, M.R. Sapio contributed equally to this work.

Received April 13, 2018

Accepted May 30, 2018

© 2018 International Association for the Study of Pain
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