Lateral Hypothalamic Orexin Neurons Mediate the Reward Effects of Pain Relief Induced by Electroacupuncture.

Sheng Liu,Chuan Qin,Meiyu Chen,Can Wang,Xueyong Shen,Xiaoyi Qu

doi:10.3389/fnmol.2022.812035

Abstract

The reward of pain relief caused by acupuncture has been found to be clinically significant. However, the molecular mechanisms underlying acupuncture-induced reward of pain relief in chronic pain remain unclear and have not been analyzed in suitable preclinical models. Here, we investigated whether acupuncture could potentially induce the reward of pain relief and orexin neuronal signaling in the lateral hypothalamus (LH) and exhibit a possible role in electroacupuncture (EA)-induced reward in spared nerve injury (SNI) rats. Therefore, by using conditioned place preference (CPP) paradigm, we noticed that EA induced the preference for cues associated with EA-induced pain relief in the early, but not late, phase of chronic pain. These observations were different from the immediate antihyperalgesic effects of EA. c-Fos/orexin double labeling revealed that EA stimulation on 14 days but not on 28 days after SNI modeling activated greater numbers of c-Fos positive orexin neurons in the LH after the CPP test. Moreover, the administration of an orexin-A antagonist in the LH significantly blocked the reward effects of pain relief induced by EA. Furthermore, by using cholera toxin b subunit combined with c-Fos detection, we found that the orexin circuit from the LH to the nucleus accumbens (NAc) shell was significantly activated after EA induced CPP. Microinjection of the orexin antagonist into the NAc shell substantially attenuated the CPP induced by EA. Intravenous injection of low-dose orexin-A together with EA resulted in significantly greater antihyperalgesia effects and CPP scores. Together, these findings clearly demonstrated that LH orexin signaling could potentially play a critical role in the reward effects of pain relief induced by acupuncture. The observations of the present study extended our understanding of orexin signaling in the LH and its role in EA-induced reward, providing new insights into the mechanisms of acupuncture analgesia.

Highlights

The reward effect of pain relief induced by acupuncture has not been well studied in preclinical models
The aim of the present study was to determine whether acupuncture induces rewards of pain relief, together with investigating whether the orexin neurons in the lateral hypothalamus (LH) are involved in this process
Using the conditioned place preference (CPP) paradigm, we found that EA was able to induce the reward effects of pain relief at an early phase of chronic pain but not at a late phase, which was different from the antihyperalgesic effect of EA observed during the different stages

Summary

Introduction

It is well established that the current conceptualizations of pain in humans are predominantly multidimensional, mainly including the perception of the noxious stimulus and the affective features of pain. Both onset of pain and pain relief have been reported to be motivationally salient events, which can lead to generating avoidance (withdrawal) and approach. Reward of Pain Relief Induced by EA behavior (Porreca and Navratilova, 2017). The conditioned place preference (CPP) paradigm has been widely used to evaluate the reward effects of pain relief (Truini et al, 2013) and the efficacy of various analgesics, especially in alleviating the aversive aspects of pain (King et al, 2009; Navratilova and Porreca, 2014; Navratilova et al, 2015). Investigations using the CPP paradigm in rats have been found to be consistent with psychological studies in humans that can conceptualize relief of pain as a reward (Leknes et al, 2008; King et al, 2009)

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