Abstract
Undoubtedly, opioid drugs have been the most popular treatment for refractory pain since found, such as morphine. However, tolerance to the analgesic effects caused by repeated use is inevitable, which greatly limits the clinical application of these drugs. Nowadays, it has become the focus of the world that further development of non-opioid-based treatment along with efficient strategies to circumvent opioid tolerance are urgently needed clinically. Fortunately, electro-acupuncture (EA) provides an alternative to pharmaceutic treatment, remaining its potential mechanisms unclear although. This study was aimed to observe the effects of EA on morphine-induced tolerance in mice and discover its underlying mechanism. Tail-flick assay and hot-plate test were conducted to assess the development of tolerance to morphine-induced analgesia effect. As a result of repeated administration scheme (10 mg/kg, twice per day, for 7 days), approximately a two-fold increase was observed in the effective dose of 50% (ED50) of morphine-induced antinociceptive effect. Interestingly, by EA treatment (2/100Hz, 0.5, 1.0, and 1.5 mA, 30 min/day for 7 days) at the acupoints Zusanli (ST36) and Sanyinjiao (SP6), morphine ED50 curves was remarkably leftward shifted on day 8. In addition, the RNA sequencing strategy was used to reveal the potential mechanisms. Due to the well described relevance of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), extracellular regulated protein kinases (ERK), and cAMP response element-binding (CREB) in brainstem (BS) to analgesia tolerance, the cAMP-PKA/ERK-CREB signaling was deeply concerned in this study. Based upon Enzyme-Linked Immunosorbent Assay, the up-regulation of the cAMP level was observed, whereas reversed with EA treatment. Similarly, western blot revealed the phosphorylation levels of PKA, ERK, and CREB were up-regulated in morphine tolerant mice, whereas the EA group showed a significantly reduced expression level instead. This study observed an attenuating effect of the EA at ST36 and SP6 on morphine tolerance in mice, and suggested several potential biological targets by RNA-seq, which include the cAMP-PKA/ERK-CREB signaling pathway, strongly supporting a useful treatment for combatting the opioid epidemic, and opioid-tolerant patients.
Highlights
Opioid analgesics, such as morphine, have been broadly used for managing moderate to severe pain management over the past decades (Caudill-Slosberg et al, 2004)
Consistent with previous observations, we found morphine-induced improve the levels of the p-extracellular regulated protein kinases (ERK), whereas there were no changes in total levels of ERK in the BS
Long-term use of morphine will produce morphine tolerance, which leads to a decrease in analgesic effect
Summary
Opioid analgesics, such as morphine, have been broadly used for managing moderate to severe pain management over the past decades (Caudill-Slosberg et al, 2004). Following long-term use of opioids, there may be disturbing side effects, including analgesia tolerance, hyperalgesia, and dependence, etc., which seriously limits their clinical application and annoys the patients (DeWire et al, 2013). Morphine tolerance is probably the main cause of diminished pain control and dose escalation resulting in more widespread side effects. Numerous evidences from trials and meta-analyses indicates that acupuncture or EA is effective for relieving pain, which may stimulate gene expression of neuropeptides and activate endogenous opioid mechanisms (Kaptchuk, 2002). The results indicated that EA analgesia shows no cross-tolerance to morphine (Cheng et al, 1980; Han et al, 1981; Li et al, 1982). Effects of acupuncture or electroacupuncture on morphine tolerance is remain unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
