The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
Rapid Broad-Spectrum Analgesia through Activation of Peroxisome Proliferator-Activated Receptor-α
Open accessAbstract
Severe pain remains a major area of unmet medical need. Here we report that agonists of the nuclear receptor PPAR-alpha (peroxisome proliferator-activated receptor-alpha) suppress pain behaviors induced in mice by chemical tissue injury, nerve damage, or inflammation. The PPAR-alpha agonists GW7647 [2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid], Wy-14643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid], and palmitoylethanolamide (PEA) reduced nocifensive behaviors elicited in mice by intraplantar (i.pl.) injection of formalin or i.p. injection of magnesium sulfate. These effects were absent in PPAR-alpha-null mice yet occurred within minutes of agonist administration in wild-type mice, suggesting that they were mediated through a transcription-independent mechanism. Consistent with this hypothesis, blockade of calcium-operated IK(ca) (K(Ca)3.1) and BK(ca) (K(Ca)1.1) potassium channels prevented the effects of GW7647 and PEA in the formalin test. Three observations suggest that PPAR-alpha agonists may inhibit nocifensive responses by acting on peripheral PPAR-alpha. (i) PEA reduced formalin-induced pain at i.pl. doses that produced no increase in systemic PEA levels; (ii) PPAR-alpha was expressed in dorsal root ganglia neurons of wild-type but not PPAR-alpha-null mice; and (ii) GW7647 and PEA prevented formalin-induced firing of spinal cord nociceptive neurons in rats. In addition to modulating nociception, GW7647 and PEA reduced hyperalgesic responses in the chronic constriction injury model of neuropathic pain; these effects were also contingent on PPAR-alpha expression and were observed following either acute or subchronic PPAR-alpha agonist administration. Finally, acute administration of GW7647 and PEA reduced hyperalgesic responses in the complete Freund's adjuvant and carrageenan models of inflammatory pain. Our results suggest that PPAR-alpha agonists may represent a novel class of analgesics.
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“This finding is perhaps unsurprising given that PPAR-α mediates effects of PEA in suppressing neuronal sensitization.130”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [130]
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Cites
A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man
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A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia
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The PPARs: From Orphan Receptors to Drug Discovery
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Self-citationRole of the Immune system in chronic pain
Marchand, F., Perretti, M., & McMahon, S. B. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1700 · Cited by 1,098
Control of pain initiation by endogenous cannabinoids
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Self-citationCarrageenan-Induced Paw Edema in the Rat and Mouse
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Cannabinoids go nuclear: evidence for activation of peroxisome proliferator‐activated receptors
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The Endocannabinoid System and Pain
Guindon, J., & Hohmann, A. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709789824660 · Cited by 476
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O'Sullivan, S. E. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13497 · Cited by 449
Metadata
- Authors
- LoVerme, J., Russo, R., La Rana, G., Fu, J., Farthing, J., Mattace-Raso, G., Meli, R., Hohmann, A., Calignano, A., & Piomelli, D.
- Affiliations
- University of Georgia (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2006-12
- Volume
- 319
- Issue
- 3
- Pages
- 1051-1061
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2105771810
- Cited by
- 316
- References
- 39
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 9 · 2023: 5 · 2022: 14 · 2021: 21 · 2020: 15 · 2019: 17 · 2018: 14 · 2017: 11 · 2016: 14 · 2015: 24 · 2014: 34 · 2013: 16 · 2012: 25
- FWCI
- 13.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.escholarship.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Sandler Foundation
- National Institute on Drug Abuse (DA14265, DA-14022, R01DA014022, R03DA014265)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- PPARα agonist, analgesia, pain, GW7647, Wy-14,643, palmitoylethanolamide, formalin test, neuropathic pain, inflammatory pain, chronic constriction injury, dorsal root ganglia, potassium channels, hyperalgesia, nociception
- MeSH terms
- Analgesics, Animals, Hypolipidemic Agents, Drug Tolerance, Formaldehyde, Hyperalgesia, Male, Mice, Inbred C57BL, Nociceptors, Pain Measurement, Fenofibrate, RNA, Sciatica, Immunoblotting, Rats, Sprague-Dawley, DNA, Complementary, Mice, Knockout, Potassium Channels, Calcium-Activated, PPAR alpha, Mice, Rats
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