Cannabinoid CB2 Receptors Contribute to Upregulation of β-endorphin in Inflamed Skin Tissues by Electroacupuncture

Abstract

BackgroundElectroacupuncture (EA) can produce analgesia by increasing the β-endorphin level and activation of peripheral μ-opioid receptors in inflamed tissues. Endogenous cannabinoids and peripheral cannabinoid CB2 receptors (CB2Rs) are also involved in the antinociceptive effect of EA on inflammatory pain. However, little is known about how peripheral CB2Rs interact with the endogenous opioid system at the inflammatory site and how this interaction contributes to the antinociceptive effect of EA on inflammatory pain. In this study, we determined the role of peripheral CB2Rs in the effects of EA on the expression of β-endorphin in inflamed skin tissues and inflammatory pain.ResultsInflammatory pain was induced by injection of complete Freund's adjuvant into the left hindpaw of rats. Thermal hyperalgesia was tested with a radiant heat stimulus, and mechanical allodynia was quantified using von Frey filaments. The mRNA level of POMC and protein level of β-endorphin were quantified by real-time PCR and Western blotting, respectively. The β-endorphin-containing keratinocytes and immune cells in the inflamed skin tissues were detected by double-immunofluorescence labeling. The CB2R agonist AM1241 or EA significantly reduced thermal hyperalgesia and mechanical allodynia, whereas the selective μ-opioid receptor antagonist β-funaltrexamine significantly attenuated the antinociceptive effect produced by them. AM1241 or EA significantly increased the mRNA level of POMC and the protein level of β-endorphin in inflamed skin tissues, and these effects were significantly attenuated by pretreatment with the CB2R antagonist AM630. AM1241 or EA also significantly increased the percentage of β-endorphin-immunoreactive keratinocytes, macrophages, and T-lymphocytes in inflamed skin tissues, and these effects were blocked by AM630.ConclusionsEA and CB2R stimulation reduce inflammatory pain through activation of μ-opioid receptors. EA increases endogenous opioid expression in keratinocytes and infiltrating immune cells at the inflammatory site through CB2R activation.

Peripheral and Spinal Mechanisms of Pain and Dry Needling Mediated Analgesia: A Clinical Resource Guide for Health Care Professionals

“…Remarkably, keratinocytes also have the ability express opioid receptors and release opioids [172,173,182]. A recent study by Moffett et al (2012) used pulsed radio frequency energy to increase precursor mRNA for enkaphalin and dynorphin in both human dermal fibroblasts and keratinocytes, suggesting that both non-neural cell types have the ability to create and release opioids [183].…”

“…Zhang et al further reported an upregulation in the expression of CB2 receptors on macrophages, T-lymphocytes and keratinocytes already present in inflamed skin tissue [179]. In addition, DN stimulates the release of endogenous anandmide, a CB2 receptor ligand and an analogue of tetrahydrocannabinol (THC) [172,173]. A recent study by Su et al found that EDN resulted in an increase in mRNA levels of POMC, a β-endorphin precursor, and protein levels of β-endorphin in keratinocytes, macrophages and T-lymphocytes [172].…”

“…dynorphin, enkephalins, and endorphins) from immune cells such as neutrophils, eosinophils, basophils, lymphocytes, monocytes and macrophages, which subsequently stimulate μ, δ and κ opioid receptors expressed on peripheral nerve terminals [146,172,173]. Studies that have pharmaceutically blocked endogenous opioids and opioid receptors have been shown to prevent mechanical and thermal analgesia in animal models secondary to DN [146,174].…”

“…A recent study by Su et al found that EDN resulted in an increase in mRNA levels of POMC, a β-endorphin precursor, and protein levels of β-endorphin in keratinocytes, macrophages and T-lymphocytes [172]. However, sham EDN and the combination of EDN and AM630, a CB2 antagonist, significantly diminished the effects [172]. Thus, by creating an environment rich with CB2 receptors and stimulating endogenous anandmide, EDN may be able to affectively amplify the production and subsequent release of opioids to block pain.…”

“…In addition, DN stimulates the release of endogenous anandmide, a CB2 receptor ligand and an analogue of tetrahydrocannabinol (THC) [172,173]. A recent study by Su et al found that EDN resulted in an increase in mRNA levels of POMC, a β-endorphin precursor, and protein levels of β-endorphin in keratinocytes, macrophages and T-lymphocytes [172]. However, sham EDN and the combination of EDN and AM630, a CB2 antagonist, significantly diminished the effects [172].…”