Electroacupuncture Inhibits Opioid‐induced Hyperalgesia in a Mouse Model of Thermal Nociception

Opioids remain the gold standard for the treatment of moderate to severe acute pain, however, repeated administration of opioids would inflict pain sensitization to the patients, a condition termed opioid‐induced hyperalgesia (OIH). One of the strategies to prevent OIH in clinical practice is by co‐administration of non‐opioid analgesics. We have recently revealed an unprecedented non‐opioid‐mediated analgesic effect induced by electroacupuncture at PC6 (Neiguan) acupoint (EA‐PC6), which overlays the median nerve, in mice.1 Briefly, EA‐PC6 at low frequency (2 Hz, 2 mA, 0.15 ms) can trigger orexin release from the lateral hypothalamus into the ventrolateral periaqueductal gray (vlPAG), a midbrain region for initiating descending pain inhibition. Orexin then activates postsynaptic orexin 1 receptors (OX1Rs), a Gq proteincoupled receptor family, in the vlPAG, resulting in synthesis of 2‐arachydonoylglycerol (2‐AG), an endocannabinoid that produces retrograde inhibition of GABA release by activating presynaptic cannabinoid 1 receptors (CB1Rs), leading to disinhibition of the vlPAG and ultimately inducing analgesia. Importantly, this EA‐PC6‐induced analgesic effect (EA‐PC6‐IA) is not blocked by naloxone, a non‐selective opioid receptor antagonist. Given the opioid‐independent nature of EA‐PC6‐IA, we further examined whether EA‐PC6 can prevent the development of OIH in male mice on thermal nociception test. OIH in mice were induced via repeated injection of morphine (twice/day, 10 mg/kg each, i.p .) over the course of 3 days, and a final dose (10mg/kg, i.p .) on the 4 th day. Immediately after the final morphine injection, EA‐PC6 was given for 20 min in OIH‐induced mice, The mice were subsequently subjected to hotplate test. The control groups included the negative control group which received isoflurane anesthesia only, the sham group with needle insertion at PC6 without electrostimulation and the non‐acupoint group (electrostimulation at the deltoid muscle where there are very few acupoints). The results showed that EA‐PC6 inhibited repeated morphine injection‐induced thermal hyperalgesia. Importantly, this analgesic effect was blocked by a pre‐treatment of either SB334867 (an OX1R antagonist, 15 mg/kg, i.p .) or AM251 (an CB1R antagonist, 1.1 mg/kg, i.p .). These findings suggest that EA‐PC6 is a potential novel pain management strategy in OIH‐inflicted patients, such as terminal cancer patients. Support or Funding Information This study was supported by Ministry of Science and Technology, Taiwan (MOST107‐2321‐B‐002‐010, MOST107‐2811‐B‐002‐008), National Health Research Institutes, Taiwan (NHRI‐EX107‐10733NI) and Ministry of Education, Taiwan. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .