Electroacupuncture in conscious free-moving mice reduces pain by ameliorating peripheral and central nociceptive mechanisms

Abstract

Integrative approaches such as electroacupuncture, devoid of drug effects are gaining prominence for treating pain. Understanding the mechanisms of electroacupuncture induced analgesia would benefit chronic pain conditions such as sickle cell disease (SCD), for which patients may require opioid analgesics throughout life. Mouse models are instructive in developing a mechanistic understanding of pain, but the anesthesia/restraint required to administer electroacupuncture may alter the underlying mechanisms. To overcome these limitations, we developed a method to perform electroacupuncture in conscious, freely moving, unrestrained mice. Using this technique we demonstrate a significant analgesic effect in transgenic mouse models of SCD and cancer as well as complete Freund’s adjuvant-induced pain. We demonstrate a comprehensive antinociceptive effect on mechanical, cold and deep tissue hyperalagesia in both genders. Interestingly, individual mice showed a variable response to electroacupuncture, categorized into high-, moderate-, and non-responders. Mechanistically, electroacupuncture significantly ameliorated inflammatory and nociceptive mediators both peripherally and centrally in sickle mice correlative to the antinociceptive response. Application of sub-optimal doses of morphine in electroacupuncture-treated moderate-responders produced equivalent antinociception as obtained in high-responders. Electroacupuncture in conscious freely moving mice offers an effective approach to develop a mechanism-based understanding of analgesia devoid of the influence of anesthetics or restraints.

Functional MRI BOLD response in sickle mice with hyperalgesia

“…The individual variation of sickle mice was also seen with acupuncture treatment [7], which might be attributed to the heterogeneity observed between patients with SCA. Although most fMRI studies rely on BOLD contrast to map the activated brain regions, it is noteworthy that the BOLD signal itself is a relatively scaled quantity reflecting the percent change between two pathophysiological conditions under investigation.…”

“…Hyperalgesia assessed with paw withdrawal frequency (PWF) as well as H/R treatment were described previously [7,8]. PWF was measured before the fMRI scan and 1 & 18 h after two treatments of H/R.…”

Mast cell‐neural interactions contribute to pain and itch

“…This could be because the CFA model‐stimulated responses were confined to the paw, which contrast with testing in actual disease models with constitutive mast cell activation and testing paradigms using responses akin to the disease being examined. We have demonstrated that analgesic responses vary between transgenic mouse models of SCD or cancer showing the evolutionary spectrum of the human disease as compared to one time CFA‐induced hyperalgesia in C57BL/6 mice …”

“…We have demonstrated that analgesic responses vary between transgenic mouse models of SCD or cancer showing the evolutionary spectrum of the human disease as compared to one time CFA-induced hyperalgesia in C57BL/6 mice. 154…”

Targeting pain at its source in sickle cell disease

“…The molecular signatures of these electrophysiological outcomes are emerging. We found that oxidative stress, SP, glial activation, glial fibrillary acidic protein, and inflammation are increased significantly in the dorsal horn of sickle BERK mice compared with control BERK mice (84,85). The spontaneous nociceptor activity in the periphery and spinal cord and hypersensitivity to mechanical and/or thermal stimuli are suggestive of central sensitization in sickle mice, which may underlie chronic pain and be recalcitrant to analgesic therapy.…”