Abstract
Acupuncture is widely used for pain treatment in patients with osteoarthritis or low back pain, but molecular mechanisms remain largely enigmatic. In the early phase of inflammation neutrophilic chemokines direct opioid-containing neutrophils in the inflamed tissue and stimulate opioid peptide release and antinociception. In this study the molecular pathway and neuroimmune connections in complete Freund's adjuvant (CFA)-induced hind paw inflammation and electroacupuncture for peripheral pain control were analyzed. Free moving Wistar rats with hind paw inflammation were treated twice with electroacupuncture at GB30 (Huan Tiao - gall bladder meridian) (day 0 and 1) and analyzed for mechanical and thermal nociceptive thresholds. The cytokine profiles as well as the expression of opioid peptides were quantified in the inflamed paw. Electroacupuncture elicited long-term antinociception blocked by local injection of anti-opioid peptide antibodies (beta-endorphin, met-enkephalin, dynorphin A). The treatment altered the cytokine profile towards an anti-inflammatory pattern but augmented interferon (IFN)-gamma and the chemokine CXCL10 (IP-10: interferon gamma-inducible protein) protein and mRNA expression with concomitant increased numbers of opioid peptide-containing CXCR3+ macrophages. In rats with CFA hind paw inflammation without acupuncture repeated injection of CXCL10 triggered opioid-mediated antinociception and increase opioid-containing macrophages. Conversely, neutralization of CXCL10 time-dependently decreased electroacupuncture-induced antinociception and the number of infiltrating opioid peptide-expressing CXCR3+ macrophages. In summary, we describe a novel function of the chemokine CXCL10 - as a regulator for an increase of opioid-containing macrophages and antinociceptive mediator in inflammatory pain and as a key chemokine regulated by electroacupuncture.
Highlights
Acupuncture has been shown to significantly reduce pain intensity in various pain syndromes e.g. in patients with osteoarthritis [1], low back pain [2] in most, but not all studies [3]
Antinociception by electroacupuncture is linked to peripheral opioid peptides In a previous study, at 96 h complete Freund’s adjuvant (CFA), electroacupuncture at GB30 caused antinociception in CFA inflammation which was fully blocked by peripheral injection (i.pl.) of the opioid receptor antagonist naloxone at the site of inflammation [10]
Local injection of antibodies against the opioid peptides END or ENK significantly inhibited electroacupuncture-mediated mechanical and thermal antinociception at 5 min post injection compared to isotype control antibody (Fig. 1B, C, F, G, doses according to [18])
Summary
Acupuncture has been shown to significantly reduce pain intensity in various pain syndromes e.g. in patients with osteoarthritis [1], low back pain [2] in most, but not all studies [3]. Acupuncture leads to a down-regulation of pro-inflammatory cytokines such as tumor necrosis factor (TNF-alpha) and interleukin (IL)-1beta at the site of inflammation [5,6]. This antiinflammatory as well as antinociceptive effect involved activation of the cannabinoid receptor 2 (CB2) [6]. Endogenous opioid peptides such as beta-endorphin (END) could contribute to acupuncture-induced analgesia. Acupuncture triggers END transcription and translational in the inflamed tissue and this was attenuated by a CB2 antagonists [11]
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