Different effects of opioid and cannabinoid receptor agonists on C-fiber-induced extracellular signal-regulated kinase activation in dorsal horn neurons in normal and spinal nerve-ligated rats
Abstract
Nerve injury results in neuropathic pain, a debilitating pain condition. Whereas cannabinoids are consistently shown to attenuate neuropathic pain, the efficacy of opioids is highly controversial. Molecular mechanisms underlying analgesic effects of opioids and cannabinoids are not fully understood. We have shown that the signaling molecule ERK (extracellular signal-regulated kinase) is activated by C-fiber stimulation in dorsal horn neurons and contributes to pain sensitization. In this study, we examined whether opioids and cannabinoids can affect C-fiber-induced ERK phosphorylation (pERK) in dorsal horn neurons in spinal cord slices from normal and spinal nerve-ligated rats. In normal control spinal slices, capsaicin induced a drastic pERK expression in superficial dorsal horn neurons, which was suppressed by morphine (10 microM), the selective mu-opioid receptor agonist DAMGO [[d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (1 microM)], and the selective CB1 receptor ACEA agonist [arachidonyl-2'-chloroethylamide (5 microM)]. One week after spinal nerve ligation when neuropathic pain is fully developed, capsaicin induced less pERK expression in the injured L(5)-spinal segment. This pERK induction was not suppressed by morphine (10 microM) and DAMGO (1 microM) but was enhanced by high concentration of DAMGO (5 microM). In contrast, ACEA (10 microM) was still very effective in inhibiting capsaicin-induced pERK expression. In the adjacent L(4) spinal segment, both DAMGO and ACEA significantly suppressed pERK induction by capsaicin. These results indicate that, after nerve injury, opioids lose their capability to suppress C-fiber-induced spinal neuron activation in the injured L(5) but not in the intact L(4) spinal segment, whereas cannabinoids still maintain their efficacy.
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Opioids (morphine and DAMGO) lose the ability to inhibit C-fiber induced ERK activation in the L5 spinal cord following SNL.
“This observation contrasts with effects of opioids (i.e. morphine and DAMGO) which lose the ability to inhibit C-fiber induced ERK activation in the L5 spinal cord following SNL.84”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [84]
The CB1-specific agonist ACEA inhibits pERK expression induced by in vitro application of capsaicin to the spinal cords of SNL rats.
“The CB1-specific agonist ACEA inhibits pERK expression induced by in vitro application of capsaicin to the spinal cords of SNL rats.”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [84]
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- Authors
- Kawasaki, Y., Kohno, T., & Ji, R.-R.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 316
- Issue
- 2
- Pages
- 601-607
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2122824308
- Cited by
- 44
- References
- 42
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 1 · 2021: 4 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 4 · 2013: 1 · 2012: 4
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fogarty International Center (TW7180, R03TW007180)
- National Institute of Neurological Disorders and Stroke (R01NS040698, NS40698)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- opioid analgesia, cannabinoid analgesia, ERK1/2 phosphorylation, dorsal horn neurons, spinal nerve ligation, neuropathic pain, morphine, DAMGO, mu-opioid receptor, CB1 receptor, ACEA, capsaicin, pain sensitization, descending pain modulation
- MeSH terms
- Animals, Arachidonic Acids, Capsaicin, Enzyme Activation, Lumbosacral Region, Male, Morphine, Phosphorylation, Receptors, Opioid, Spinal Nerves, Rats, Sprague-Dawley, Mononeuropathies, Posterior Horn Cells, Enkephalin, Ala(2)-MePhe(4)-Gly(5)-, Extracellular Signal-Regulated MAP Kinases, Rats, Cannabinoid Receptor Agonists
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