Abstract
Resiniferatoxin (RTX) is a potent agonist of TRPV1, which possesses unique properties
that can be utilized to treat certain modalities of pain. In the present study, systemic
intraperitoneal (i.p.) administration of RTX resulted in a significant decrease in
acute thermal pain sensitivity, whereas localized intrathecal (i.t.) administration
had no effect on acute thermal pain sensitivity. Both i.p. and i.t. administration
of RTX prevented TRPV1-induced nocifensive behavior and inflammatory thermal hypersensitivity.
There were no alterations in mechanical sensitivity either by i.p. or i.t. administration
of RTX. In spinal dorsal horn (L4-L6), TRPV1 and substance P immunoreactivity were
abolished following i.p. and i.t. administration of RTX. In dorsal root ganglia (DRG),
TRPV1 immunoreactivity was diminished following i.p. administration, but was unaffected
following i.t. administration of RTX. Following i.p. administration, basal and evoked
calcitonin gene-related peptide release were reduced both in the spinal cord and peripheral
tissues. However, following i.t. administration, basal and evoked calcitonin gene-related
peptide release were reduced in spinal cord (L4-L6), but were unaffected in peripheral
tissues. Both i.p. and i.t. RTX administration lowered the body temperature acutely,
but this effect reversed with time. Targeting TRPV1-expressing nerve terminals at
the spinal cord can selectively abolish inflammatory thermal hypersensitivity without
affecting acute thermal sensitivity and can preserve the efferent functions of DRG
neurons at the peripheral nerve terminals. I.t. administration of RTX can be considered
as a strategy for treating certain chronic and debilitating pain conditions.
Perspective
Localized administration of RTX in spinal cord could be a useful strategy to treat
chronic debilitating pain arising from certain conditions such as cancer and at the
same time could maintain normal physiological peripheral efferent functions mediated
by TRPV1.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of PainAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Answering the burning question of how transient receptor potential vanilloid-1 channel antagonists cause unwanted hyperthermia.Pharmacol Rev. 2009; 61: 225-227
- Prolonged analgesic response of cornea to topical resiniferatoxin, a potent TRPV1 agonist.Pain. 2010; 149: 522-528
- TRPs in bladder diseases.Biochim Biophys Acta. 2007; 1772: 879-884
- Possible Consequences of Blocking Transient Receptor Potential Vanilloid 1.Curr Pharm Biotechnol. 2011; 12: 102-114
- Synthetic interstitial fluid for isolated mammalian tissue.Life Sci. 1969; 8: 319-329
- Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a canine bone cancer model.Anesthesiology. 2005; 103: 1052-1059
- Impaired nociception and pain sensation in mice lacking the capsaicin receptor.Science. 2000; 288: 306-313
- The capsaicin receptor: A heat-activated ion channel in the pain pathway.Nature. 1997; 389: 816-824
- Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli.Proc Natl Acad Sci U S A. 2009; 106: 9075-9080
- Loss of TRPV1-expressing sensory neurons reduce spinal mu opioid receptors but paradoxically potentiate opioid analgesia.J Neurophysiol. 2006; 95: 3086-3096
- Intrathecal delivery of resiniferatoxin (RTX) reduces detrusor overactivity and spinal expression of TRPV1 in spinal cord injured animals.Exp Neurol. 2008; 214: 301-308
- Lipopolysaccharide fever is initiated via a capsaicin-sensitive mechanism independent of the subtype-1 vanilloid receptor.Br J Pharmacol. 2004; 143: 1023-1032
- Sensitized peripheral nociception in experimental diabetes of the rat.Pain. 2010; 151: 496-505
- Vanilloid receptor TRPV1: Hot on the tongue and inflaming the colon.Neurogastroenterol Motil. 2004; 16: 697-699
- The TRPV1 receptor and nociception.Semin Cell Dev Biol. 2006; 17: 582-591
- Intracisternal capsaicin: Selective degeneration of chemosensitive primary sensory afferents in the adult rat.Neurosci Lett. 1981; 27: 41-45
- Vapour Pressure of H2(18)O ice (I) (−17 degrees C to 0 degrees C) and H2(18)O water (0 degrees C to 16 degrees C).Nature. 1970; 225: 723
- Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia.PLoS One. 2009; 4: e7021
- Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control.J Clin Invest. 2004; 113: 1344-1352
- Hot flash: TRPV channels in the brain.Trends Neurosci. 2009; 32: 215-224
- The effects of intra-articular resiniferatoxin in experimental knee-joint arthritis.Anesth Analg. 2005; 101: 1433-1439
- Vanilloid-induced conduction analgesia: Selective, dose-dependent, long-lasting, with a low level of potential neurotoxicity.Anesth Analg. 2008; 107: 271-281
- Anesthetic management of patients with interstitial cystitis during intravesical resiniferatoxin therapy.Masui. 2005; 54: 149-152
- Release of calcitonin gene-related peptide from sensory neurons.Ann N Y Acad Sci. 1992; 657: 187-193
- Vanilloid receptor (TRPV1)-deficient mice show increased susceptibility to dinitrobenzene sulfonic acid-induced colitis.J Mol Med. 2006; 84: 142-146
- A method to perform direct transcutaneous intrathecal injection in rats.J Pharmacol Toxicol Methods. 1994; 32: 197-200
- Ablation of TrpV1 neurons reveal their selective role in thermal pain sensation.Mol Cell Neurosci. 2010; 43: 157-163
- Perineural resiniferatoxin selectively inhibits inflammatory hyperalgesia.Mol Pain. 2008; 4: 3
- Ligand-induced dynamic membrane changes and cell deletion conferred by vanilloid receptor 1.J Biol Chem. 2001; 276: 11021-11030
- Lack of involvement of capsaicin-sensitive primary afferents in nerve-ligation injury induced tactile allodynia in rats.Pain. 1999; 79: 127-133
- Direct role of streptozotocin in inducing thermal hyperalgesia by enhanced expression of transient receptor potential vanilloid 1 in sensory neurons.Mol Pharmacol. 2008; 73: 995-1004
- Resiniferatoxin induces paradoxical changes in thermal and mechanical sensitivities in rats: Mechanism of action.J Neurosci. 2003; 123: 2911-2919
- Effects of TRPV1 receptor antagonists on stimulated iCGRP release from isolated skin of rats and TRPV1 mutant mice.Pain. 2004; 109: 284-290
- Targeting TRPV1 as an alternative approach to narcotic analgesics to treat chronic pain conditions.AAPS J. 2010; 12: 361-370
- TRPV1: A target for next generation analgesics.Curr Neuropharmacol. 2008; 6: 151-163
- Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin.J Physiol. 2005; 567: 771-786
- TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes.Cell. 2006; 127: 1123-1135
- The transient receptor potential vanilloid-1 channel in thermoregulation: A thermosensor it is not.Pharmacol Rev. 2009; 61: 228-261
- Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.Cell. 2009; 137: 1148-1159
- The effects of resiniferatoxin in an experimental rat thoracotomy model.Anesth Analg. 2010; 1110: 228-232
- Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse.J Physiol. 2007; 1581: 631-647
- Role of different proton-sensitive channels in releasing calcitonin gene-related peptide from isolated hearts of mutant mice.Cardiovasc Res. 2005; 65: 405-410
- Alteration of capsaicin and endotoxin-induced calcitonin gene-related peptide release from mesenteric arterial bed and spinal cord slice in 18-month-old rats.J Neurosci Res. 1998; 53: 385-392
- Cellular basis of itch sensation.Science. 2009; 325: 1531-1534
- Epidural resiniferatoxin induced prolonged regional analgesia to pain.Brain Res. 1999; 840: 92-98
- Vanilloid (Capsaicin) receptors and mechanisms.Pharmacol Rev. 1999; 51: 159-212
- The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept.Nat Rev Drug Discov. 2007; 6: 357-372
- The effect of pulsed radiofrequency current on mechanical allodynia induced with resiniferatoxin in rats.Anesth Analg. 2010; 111: 784-790
- Vanilloid receptor 1-positive neurons mediate thermal hyperalgesia and tactile allodynia.Spine J. 2008; 8: 351-358
- Selective ablation of nociceptive neurons for elimination of hyperalgesia and neurogenic inflammation.J Neurosurg. 2005; 102: 522-525
- Neural control of blood pressure: Focusing on capsaicin-sensitive sensory nerves.Cardiovasc Hematol Disord Drug Targets. 2007; 7: 37-46
- Cellular mechanism of action of resiniferatoxin: A potent sensory neuron excitotoxin.Brain Res. 1990; 520: 131-140
- Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.Brain Res Rev. 2009; 60: 267-277
Article info
Publication history
Published online: June 17, 2011
Accepted:
March 16,
2011
Received in revised form:
January 25,
2011
Received:
October 29,
2010
Footnotes
Supported by grants from National Institutes of Health (DA028017) and EAM award from SIUSOM.
There is no conflict of interest among authors.
Identification
Copyright
© 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.