Pain control through selective chemo-axotomy of centrally projecting TRPV1+ sensory neurons

Agonists of the vanilloid receptor transient vanilloid potential 1 (TRPV1) are emerging as highly efficacious nonopioid analgesics in preclinical studies. These drugs selectively lesion TRPV1+ primary sensory afferents, which are responsible for the transmission of many noxious stimulus modalities....

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Published inThe Journal of clinical investigation Vol. 128; no. 4; pp. 1657 - 1670
Main Authors Sapio, Matthew R., Neubert, John K., LaPaglia, Danielle M., Maric, Dragan, Keller, Jason M., Raithel, Stephen J., Rohrs, Eric L., Anderson, Ethan M., Butman, John A., Caudle, Robert M., Brown, Dorothy C., Heiss, John D., Mannes, Andrew J., Iadarola, Michael J.
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 02.04.2018
Subjects
Analgesics, Non-Narcotic - pharmacology
Animals
Axotomy
Cancer Pain - drug therapy
Cancer Pain - metabolism
Cancer Pain - pathology
Diterpenes - pharmacology
Dogs
Ganglia, Spinal - metabolism
Ganglia, Spinal - pathology
Humans
Pain Management
Rats
Sensory Receptor Cells - metabolism
Sensory Receptor Cells - pathology
TRPV Cation Channels
Neuroscience
Expression profiling
Pain
Addiction
Clinical Trials
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Abstract Agonists of the vanilloid receptor transient vanilloid potential 1 (TRPV1) are emerging as highly efficacious nonopioid analgesics in preclinical studies. These drugs selectively lesion TRPV1+ primary sensory afferents, which are responsible for the transmission of many noxious stimulus modalities. Resiniferatoxin (RTX) is a very potent and selective TRPV1 agonist and is a promising candidate for treating many types of pain. Recent work establishing intrathecal application of RTX for the treatment of pain resulting from advanced cancer has demonstrated profound analgesia in client-owned dogs with osteosarcoma. The present study uses transcriptomics and histochemistry to examine the molecular mechanism of RTX action in rats, in clinical canine subjects, and in 1 human subject with advanced cancer treated for pain using intrathecal RTX. In all 3 species, we observe a strong analgesic action, yet this was accompanied by limited transcriptional alterations at the level of the dorsal root ganglion. Functional and neuroanatomical studies demonstrated that intrathecal RTX largely spares susceptible neuronal perikarya, which remain active peripherally but unable to transmit signals to the spinal cord. The results demonstrate that central chemo-axotomy of the TRPV1+ afferents underlies RTX analgesia and refine the neurobiology underlying effective clinical use of TRPV1 agonists for pain control.
AbstractList Agonists of the vanilloid receptor transient vanilloid potential 1 (TRPV1) are emerging as highly efficacious nonopioid analgesics in preclinical studies. These drugs selectively lesion TRPV1+ primary sensory afferents, which are responsible for the transmission of many noxious stimulus modalities. Resiniferatoxin (RTX) is a very potent and selective TRPV1 agonist and is a promising candidate for treating many types of pain. Recent work establishing intrathecal application of RTX for the treatment of pain resulting from advanced cancer has demonstrated profound analgesia in client-owned dogs with osteosarcoma. The present study uses transcriptomics and histochemistry to examine the molecular mechanism of RTX action in rats, in clinical canine subjects, and in 1 human subject with advanced cancer treated for pain using intrathecal RTX. In all 3 species, we observe a strong analgesic action, yet this was accompanied by limited transcriptional alterations at the level of the dorsal root ganglion. Functional and neuroanatomical studies demonstrated that intrathecal RTX largely spares susceptible neuronal perikarya, which remain active peripherally but unable to transmit signals to the spinal cord. The results demonstrate that central chemo-axotomy of the TRPV1+ afferents underlies RTX analgesia and refine the neurobiology underlying effective clinical use of TRPV1 agonists for pain control.Agonists of the vanilloid receptor transient vanilloid potential 1 (TRPV1) are emerging as highly efficacious nonopioid analgesics in preclinical studies. These drugs selectively lesion TRPV1+ primary sensory afferents, which are responsible for the transmission of many noxious stimulus modalities. Resiniferatoxin (RTX) is a very potent and selective TRPV1 agonist and is a promising candidate for treating many types of pain. Recent work establishing intrathecal application of RTX for the treatment of pain resulting from advanced cancer has demonstrated profound analgesia in client-owned dogs with osteosarcoma. The present study uses transcriptomics and histochemistry to examine the molecular mechanism of RTX action in rats, in clinical canine subjects, and in 1 human subject with advanced cancer treated for pain using intrathecal RTX. In all 3 species, we observe a strong analgesic action, yet this was accompanied by limited transcriptional alterations at the level of the dorsal root ganglion. Functional and neuroanatomical studies demonstrated that intrathecal RTX largely spares susceptible neuronal perikarya, which remain active peripherally but unable to transmit signals to the spinal cord. The results demonstrate that central chemo-axotomy of the TRPV1+ afferents underlies RTX analgesia and refine the neurobiology underlying effective clinical use of TRPV1 agonists for pain control.
Agonists of the vanilloid receptor transient vanilloid potential 1 (TRPV1) are emerging as highly efficacious nonopioid analgesics in preclinical studies. These drugs selectively lesion TRPV1 + primary sensory afferents, which are responsible for the transmission of many noxious stimulus modalities. Resiniferatoxin (RTX) is a very potent and selective TRPV1 agonist and is a promising candidate for treating many types of pain. Recent work establishing intrathecal application of RTX for the treatment of pain resulting from advanced cancer has demonstrated profound analgesia in client-owned dogs with osteosarcoma. The present study uses transcriptomics and histochemistry to examine the molecular mechanism of RTX action in rats, in clinical canine subjects, and in 1 human subject with advanced cancer treated for pain using intrathecal RTX. In all 3 species, we observe a strong analgesic action, yet this was accompanied by limited transcriptional alterations at the level of the dorsal root ganglion. Functional and neuroanatomical studies demonstrated that intrathecal RTX largely spares susceptible neuronal perikarya, which remain active peripherally but unable to transmit signals to the spinal cord. The results demonstrate that central chemo-axotomy of the TRPV1 + afferents underlies RTX analgesia and refine the neurobiology underlying effective clinical use of TRPV1 agonists for pain control.
Agonists of the vanilloid receptor transient vanilloid potential 1 (TRPV1) are emerging as highly efficacious nonopioid analgesics in preclinical studies. These drugs selectively lesion TRPV1+ primary sensory afferents, which are responsible for the transmission of many noxious stimulus modalities. Resiniferatoxin (RTX) is a very potent and selective TRPV1 agonist and is a promising candidate for treating many types of pain. Recent work establishing intrathecal application of RTX for the treatment of pain resulting from advanced cancer has demonstrated profound analgesia in client-owned dogs with osteosarcoma. The present study uses transcriptomics and histochemistry to examine the molecular mechanism of RTX action in rats, in clinical canine subjects, and in 1 human subject with advanced cancer treated for pain using intrathecal RTX. In all 3 species, we observe a strong analgesic action, yet this was accompanied by limited transcriptional alterations at the level of the dorsal root ganglion. Functional and neuroanatomical studies demonstrated that intrathecal RTX largely spares susceptible neuronal perikarya, which remain active peripherally but unable to transmit signals to the spinal cord. The results demonstrate that central chemo-axotomy of the TRPV1+ afferents underlies RTX analgesia and refine the neurobiology underlying effective clinical use of TRPV1 agonists for pain control.
Author Caudle, Robert M.
Butman, John A.
Sapio, Matthew R.
Neubert, John K.
LaPaglia, Danielle M.
Brown, Dorothy C.
Heiss, John D.
Mannes, Andrew J.
Raithel, Stephen J.
Anderson, Ethan M.
Maric, Dragan
Rohrs, Eric L.
Keller, Jason M.
Iadarola, Michael J.
AuthorAffiliation 4 Department of Oral and Maxillofacial Surgery, University of Florida College of Dentistry, Gainesville, Florida, USA
6 Veterinary Clinical Investigations Center, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania, USA
5 Clinical Center, Radiology and Imaging Services, NIH, Bethesda, Maryland, USA
7 Surgical Neurology Branch, NIH, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA
1 Clinical Center, Department of Perioperative Medicine, NIH, Bethesda, Maryland, USA
3 Flow Cytometry Core Facility, NIH, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA
2 Department of Orthodontics, University of Florida College of Dentistry, Gainesville, Florida, USA
AuthorAffiliation_xml – name: 5 Clinical Center, Radiology and Imaging Services, NIH, Bethesda, Maryland, USA
– name: 7 Surgical Neurology Branch, NIH, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA
– name: 6 Veterinary Clinical Investigations Center, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, Pennsylvania, USA
– name: 2 Department of Orthodontics, University of Florida College of Dentistry, Gainesville, Florida, USA
– name: 1 Clinical Center, Department of Perioperative Medicine, NIH, Bethesda, Maryland, USA
– name: 3 Flow Cytometry Core Facility, NIH, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA
– name: 4 Department of Oral and Maxillofacial Surgery, University of Florida College of Dentistry, Gainesville, Florida, USA
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Snippet Agonists of the vanilloid receptor transient vanilloid potential 1 (TRPV1) are emerging as highly efficacious nonopioid analgesics in preclinical studies....
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SubjectTerms Analgesics, Non-Narcotic - pharmacology
Animals
Axotomy
Cancer Pain - drug therapy
Cancer Pain - metabolism
Cancer Pain - pathology
Diterpenes - pharmacology
Dogs
Ganglia, Spinal - metabolism
Ganglia, Spinal - pathology
Humans
Pain Management
Rats
Sensory Receptor Cells - metabolism
Sensory Receptor Cells - pathology
TRPV Cation Channels
Title Pain control through selective chemo-axotomy of centrally projecting TRPV1+ sensory neurons
URI https://www.ncbi.nlm.nih.gov/pubmed/29408808
https://www.proquest.com/docview/1999196414
https://pubmed.ncbi.nlm.nih.gov/PMC5873867
Volume 128
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