Unilateral epidural targeting of resiniferatoxin induces bilateral neurolysis of spinal nociceptive afferents

Mark D. Unger, Josef Pleticha, Joanne Steinauer, Rahul Kanwar, Felix Diehn, Katherine T. LaVallee, Michaela S. Banck, Bryan Jones, Tony L. Yaksh, Timothy Maus, Andreas S Beutler

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Objective. This study modeled image-guided epidural drug delivery to test whether intraprocedural distribution of pre-injected contrast reliably predicts the neuroanatomical reach of resiniferatoxin-mediated nociceptive neurolysis. Methods. Swine (N ¼ 12) received unilateral L4-S2 computed tomography fluoroscopy injections by a blinded neuroradiologist; 0.25 mL of contrast was pre-injected to confirm dorsal periganglionic targeting, followed by a 0.5-mL injection of 5 mg of resiniferatoxin/Tween80 or vehicle control. Epidural contrast distribution was graded according to maximum medial excursion. Spinal cord substance P immunostaining quantified the magnitude and anatomical range of resiniferatoxin activity. Results. Periganglionic injection was well tolerated by all animals without development of neurological deficits or other complications. Swine were a suitable model of human clinical spinal intervention. The transforaminal approach was used at all L4 and 50% of L5 segments; the remaining segments were approached by the interlaminar route. All injections were successful with unilateral contrast distribution for all resiniferatoxin injections (N ¼ 28). Immunohistochemistry showed bilateral ablation of substance Pþ fibers entering the spinal cord of all resiniferatoxin-treated segments. The intensity of substance P immunostaining in treated segments fell below the lower 99% confidence interval of controls, defining the knockout phenotype. Substance P knockout occurred over a narrow range and was uncorrelated to the anatomical distribution of pre-injected contrast. Conclusions. Periganglionic resiniferatoxin/Tween80 induced bilateral ablation of spinal cord substance P despite exclusively unilateral targeting. These data suggest that the location of pre-injected contrast is an imperfect surrogate for the neuroanatomical range of drugs delivered to the dorsal epidural compartment that may fail to predict contralateral drug effects.

Original languageEnglish (US)
Pages (from-to)897-906
Number of pages10
JournalPain Medicine (United States)
Volume20
Issue number5
DOIs
StatePublished - Jan 1 2019

Fingerprint

Substance P
Injections
Spinal Cord
Swine
Pharmaceutical Preparations
Fluoroscopy
resiniferatoxin
Immunohistochemistry
Tomography
Confidence Intervals
Phenotype

Keywords

  • Computed Tomography Fluoroscopy
  • Epidural Contrast
  • Large Animal Model
  • Nociceptive Neurolysis
  • Periganglionic
  • Resiniferatoxin

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Unilateral epidural targeting of resiniferatoxin induces bilateral neurolysis of spinal nociceptive afferents. / Unger, Mark D.; Pleticha, Josef; Steinauer, Joanne; Kanwar, Rahul; Diehn, Felix; LaVallee, Katherine T.; Banck, Michaela S.; Jones, Bryan; Yaksh, Tony L.; Maus, Timothy; Beutler, Andreas S.

In: Pain Medicine (United States), Vol. 20, No. 5, 01.01.2019, p. 897-906.

Research output: Contribution to journalArticle

Unger, MD, Pleticha, J, Steinauer, J, Kanwar, R, Diehn, F, LaVallee, KT, Banck, MS, Jones, B, Yaksh, TL, Maus, T & Beutler, AS 2019, 'Unilateral epidural targeting of resiniferatoxin induces bilateral neurolysis of spinal nociceptive afferents', Pain Medicine (United States), vol. 20, no. 5, pp. 897-906. https://doi.org/10.1093/pm/pny276
Unger, Mark D. ; Pleticha, Josef ; Steinauer, Joanne ; Kanwar, Rahul ; Diehn, Felix ; LaVallee, Katherine T. ; Banck, Michaela S. ; Jones, Bryan ; Yaksh, Tony L. ; Maus, Timothy ; Beutler, Andreas S. / Unilateral epidural targeting of resiniferatoxin induces bilateral neurolysis of spinal nociceptive afferents. In: Pain Medicine (United States). 2019 ; Vol. 20, No. 5. pp. 897-906.
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abstract = "Objective. This study modeled image-guided epidural drug delivery to test whether intraprocedural distribution of pre-injected contrast reliably predicts the neuroanatomical reach of resiniferatoxin-mediated nociceptive neurolysis. Methods. Swine (N ¼ 12) received unilateral L4-S2 computed tomography fluoroscopy injections by a blinded neuroradiologist; 0.25 mL of contrast was pre-injected to confirm dorsal periganglionic targeting, followed by a 0.5-mL injection of 5 mg of resiniferatoxin/Tween80 or vehicle control. Epidural contrast distribution was graded according to maximum medial excursion. Spinal cord substance P immunostaining quantified the magnitude and anatomical range of resiniferatoxin activity. Results. Periganglionic injection was well tolerated by all animals without development of neurological deficits or other complications. Swine were a suitable model of human clinical spinal intervention. The transforaminal approach was used at all L4 and 50{\%} of L5 segments; the remaining segments were approached by the interlaminar route. All injections were successful with unilateral contrast distribution for all resiniferatoxin injections (N ¼ 28). Immunohistochemistry showed bilateral ablation of substance P{\th} fibers entering the spinal cord of all resiniferatoxin-treated segments. The intensity of substance P immunostaining in treated segments fell below the lower 99{\%} confidence interval of controls, defining the knockout phenotype. Substance P knockout occurred over a narrow range and was uncorrelated to the anatomical distribution of pre-injected contrast. Conclusions. Periganglionic resiniferatoxin/Tween80 induced bilateral ablation of spinal cord substance P despite exclusively unilateral targeting. These data suggest that the location of pre-injected contrast is an imperfect surrogate for the neuroanatomical range of drugs delivered to the dorsal epidural compartment that may fail to predict contralateral drug effects.",
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T1 - Unilateral epidural targeting of resiniferatoxin induces bilateral neurolysis of spinal nociceptive afferents

AU - Unger, Mark D.

AU - Pleticha, Josef

AU - Steinauer, Joanne

AU - Kanwar, Rahul

AU - Diehn, Felix

AU - LaVallee, Katherine T.

AU - Banck, Michaela S.

AU - Jones, Bryan

AU - Yaksh, Tony L.

AU - Maus, Timothy

AU - Beutler, Andreas S

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Objective. This study modeled image-guided epidural drug delivery to test whether intraprocedural distribution of pre-injected contrast reliably predicts the neuroanatomical reach of resiniferatoxin-mediated nociceptive neurolysis. Methods. Swine (N ¼ 12) received unilateral L4-S2 computed tomography fluoroscopy injections by a blinded neuroradiologist; 0.25 mL of contrast was pre-injected to confirm dorsal periganglionic targeting, followed by a 0.5-mL injection of 5 mg of resiniferatoxin/Tween80 or vehicle control. Epidural contrast distribution was graded according to maximum medial excursion. Spinal cord substance P immunostaining quantified the magnitude and anatomical range of resiniferatoxin activity. Results. Periganglionic injection was well tolerated by all animals without development of neurological deficits or other complications. Swine were a suitable model of human clinical spinal intervention. The transforaminal approach was used at all L4 and 50% of L5 segments; the remaining segments were approached by the interlaminar route. All injections were successful with unilateral contrast distribution for all resiniferatoxin injections (N ¼ 28). Immunohistochemistry showed bilateral ablation of substance Pþ fibers entering the spinal cord of all resiniferatoxin-treated segments. The intensity of substance P immunostaining in treated segments fell below the lower 99% confidence interval of controls, defining the knockout phenotype. Substance P knockout occurred over a narrow range and was uncorrelated to the anatomical distribution of pre-injected contrast. Conclusions. Periganglionic resiniferatoxin/Tween80 induced bilateral ablation of spinal cord substance P despite exclusively unilateral targeting. These data suggest that the location of pre-injected contrast is an imperfect surrogate for the neuroanatomical range of drugs delivered to the dorsal epidural compartment that may fail to predict contralateral drug effects.

AB - Objective. This study modeled image-guided epidural drug delivery to test whether intraprocedural distribution of pre-injected contrast reliably predicts the neuroanatomical reach of resiniferatoxin-mediated nociceptive neurolysis. Methods. Swine (N ¼ 12) received unilateral L4-S2 computed tomography fluoroscopy injections by a blinded neuroradiologist; 0.25 mL of contrast was pre-injected to confirm dorsal periganglionic targeting, followed by a 0.5-mL injection of 5 mg of resiniferatoxin/Tween80 or vehicle control. Epidural contrast distribution was graded according to maximum medial excursion. Spinal cord substance P immunostaining quantified the magnitude and anatomical range of resiniferatoxin activity. Results. Periganglionic injection was well tolerated by all animals without development of neurological deficits or other complications. Swine were a suitable model of human clinical spinal intervention. The transforaminal approach was used at all L4 and 50% of L5 segments; the remaining segments were approached by the interlaminar route. All injections were successful with unilateral contrast distribution for all resiniferatoxin injections (N ¼ 28). Immunohistochemistry showed bilateral ablation of substance Pþ fibers entering the spinal cord of all resiniferatoxin-treated segments. The intensity of substance P immunostaining in treated segments fell below the lower 99% confidence interval of controls, defining the knockout phenotype. Substance P knockout occurred over a narrow range and was uncorrelated to the anatomical distribution of pre-injected contrast. Conclusions. Periganglionic resiniferatoxin/Tween80 induced bilateral ablation of spinal cord substance P despite exclusively unilateral targeting. These data suggest that the location of pre-injected contrast is an imperfect surrogate for the neuroanatomical range of drugs delivered to the dorsal epidural compartment that may fail to predict contralateral drug effects.

KW - Computed Tomography Fluoroscopy

KW - Epidural Contrast

KW - Large Animal Model

KW - Nociceptive Neurolysis

KW - Periganglionic

KW - Resiniferatoxin

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DO - 10.1093/pm/pny276

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JF - Pain Medicine

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