Caffeine consumption inhibits acupuncture analgesic effects by blocking adenosine signaling. However, existing evidence remains controversial. Hence, this study aimed to examine the adenosine A1 receptor (A1R) role in moderate-dose caffeine-induced abolishing effect on acupuncture analgesia using A1R knockout mice (A1R-/-). We assessed the role of A1R in physiological sensory perception and its interaction with caffeine by measuring mechanical and thermal pain thresholds and administering A1R and adenosine 2A receptor antagonists in wild-type (WT) and A1R-/- mice. Formalinand complete Freund's adjuvant (CFA)-induced inflammatory pain models were recruited to explore moderate-dose caffeine effect on pain perception and acupuncture analgesia in WT and A1R-/- mice. Moreover, a C-fiber reflex electromyogram in the biceps femoris was conducted to validate the role of A1R in the caffeine-induced blockade of acupuncture analgesia. We found that A1R was dispensable for physiological sensory perception and formalin- and CFA-induced hypersensitivity. However, genetic deletion of A1R impaired the antinociceptive effect of acupuncture in A1R-/- mice under physiological or inflammatory pain conditions. Acute moderate-dose caffeine administration induced mechanical and thermal hyperalgesia under physiological conditions but not in formalin- and CFA-induced inflammatory pain. Moreover, caffeine significantly inhibited electroacupuncture (EA) analgesia in physiological and inflammatory pain in WT mice, comparable to that of A1R antagonists. Conversely, A1R deletion impaired the EA analgesic effect and decreased the caffeine-induced inhibitory effect on EA analgesia in physiological conditions and inflammatory pain. Moderate-dose caffeine administration diminished the EA-induced antinociceptive effect by blocking A1R. Overall, our study suggested that caffeine consumption should be avoided during acupuncture treatment. Perspective: Moderate-dose caffeine injection attenuated EA-induced antinociceptive effect in formalin- and CFA-induced inflammatory pain mice models by blocking A1R. This highlights the importance of monitoring caffeine intake during acupuncture treatment. (R) 2023 Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc

神经病理性疼痛是由神经系统的原发性损害和神经功能障碍所引起的一种常见的、顽固性的慢性疼痛,临床主要表现为自发性疼痛、痛觉过敏、痛觉超敏等。其病因及发病机制尚未明确,临床亦缺乏确切有效的治疗方法。作为我国传统的疾病治疗手段,已经初步证实针刺主要是通过促进内源性阿片肽释放、抑制P物质含量、干扰腺苷代谢及调控嘌呤信号通路等来实现其镇痛作用。同时,临床研究中针刺在治疗脑卒中后疼痛、幻肢痛、脊髓损伤后疼痛、带状疱疹后疼痛、三叉神经痛、腕管综合征等中枢神经系统及周围神经系统疼痛疾病中取得了一定疗效。该文通过对近10年针刺治疗神经病理性疼痛的临床研究进展进行回顾分析,以期为科学研究和临床实践提供思路和有益参考。

1.研究背景研究表明，咖啡因能够拮抗腺苷受体削弱针刺镇痛效应，那么西方咖啡饮用习惯与中西方针刺镇痛疗效差异是否存在联系。因此，本项目在动物及人体实/试验两个层面，观察连续饮用咖啡(因)对针刺镇痛效应的影响及机制。2.研究内容 2.1 以SD大鼠CCIp模型为实验对象，测量痛阈及C反射变化，观察连续咖啡饮用对针刺治疗降低神经病理痛效应的影响;2.2 以腺苷A1受体敲除(A1R-/-)小鼠及野生型(A1R+/+)小鼠CFA模型为实验对象，结合腺苷受体激动剂、拮抗剂，测量痛阈及C反射变化，观察针刺、腺苷受体激动剂、拮抗剂干预对正常及CFA模型小鼠的影响;2.3 招募无咖啡饮用习惯的健康志愿者及慢性腰腿痛患者，给予咖啡或果汁干预，以压痛阈、热痛阈、CPM NRS评分及RⅢ反射为检测指标，观察健康或疾病条件时，连续饮用咖啡对针刺镇痛效应的影响;2.4 招募自带咖啡饮用习惯的慢性腰腿痛患者，与饮水患者对照，以压痛阈、热痛阈、CPM NRS评分及RⅢ反射为检测指标，观察慢性咖啡饮用习惯对慢性痛患者痛阈及针刺镇痛效应的影响。3.重要结果 3.1针刺干预能够显著提高CCIp模型大鼠足底痛阈，但连续饮用中等剂量水平的咖啡对针刺效应无显著影响;3.2正常条件及CFA模型后，与A1R+/+小鼠相比，针刺增加A1R-/-小鼠痛阈的效应显著降低；模型后，与A1R-/-小鼠相比，咖啡因干预显著降低了针刺对A1R+/+小鼠痛阈的增加效应。3.3饮用咖啡4周时，与果汁组相比，针刺对咖啡组志愿者BL 25及BL 57的PPT及PPTo的增加效应降低，但两组热痛阈,CPM NRS评分及RⅢ反射无显著差异。3.4 慢性痛患者试验：针灸治疗后，各组患者VAS评分显著降低，但组间相比无统计学差异；针灸治疗对各组患者痛点的PPT及PPTo无明显影响，且组间PPT及PPTo差值相比无差异。4.科学意义本项目的科学意义在于探讨咖啡因削弱针刺镇痛效应的作用机制，对揭示中西方针刺镇痛疗效差异与西方咖啡习惯的可能性联系，以及提高临床针刺镇痛效应具有重要意义。

Background: Acupuncture therapy plays a pivotal role in pain relief, and increasing evidence demonstrates that mast cells (MCs) may mediate acupuncture analgesia. The present study aims to investigate the role of MCs in acupuncture analgesia using c-kit gene mutant-induced MC-deficient rats.Materials and methods: WsRC-Ws/Ws rats and their wild-type (WT) littermates (WsRC-+/+) were used. The number of MCs in skin of ST36 area was compared in two rats after immunofluorescence labeling. Mechanical withdrawal latency (MWL), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL) were measured on bilateral plantar for pain threshold evaluation before and after each stimulus. Acupuncture-and moxibustion-like stimuli (43 degrees C, 46 degrees C heat, 1 mA electroacupuncture [EA], 3 mA EA, and manual acupuncture [MA]) were applied randomly on different days.Results: Fewer MCs were observed in the skin of ST36 in mutant rats compared to WT rats (P<0.001). For pain thresholds, MWL and MWT were higher in WsRC-Ws/Ws compared to WsRC-+/+ on bilateral paws (P<0.05), but TWL was not different between the two rats (P>0.05). Bilateral MWL and MWT in WsRC-+/+ rats increased significantly after each stimulus compared to baseline (P<0.01, P<0.001). In WsRC-Ws/Ws rats, only noxious stimuli could produce antinociceptive effects for mechanical pain (46 degrees C, 3 mA EA, MA) (P<0.01, P<0.001). Additionally, the net increases in MWL and MWT induced by most stimuli were greater in WT than in mutant rats (P<0.05). For thermal nociception, either high-or low-intensity stimuli could significantly augment TWL in two rats (P<0.001), and the net increases of TWL evoked by most stimuli were to the same extent in two genetic variants.Conclusion: MCs influence the basic mechanical but not thermal pain threshold. MCs participate in acupuncture analgesia in mechanical but not in thermal nociception, in that MC deficiency may attenuate the mechanical analgesia evoked by high-intensity stimuli and eliminate analgesia provoked by low-intensity stimuli.

干针疗法是指以人体解剖和生理学为基础,通过激痛点刺激治疗肌筋膜痛的特殊针刺方法。近些年,西方治疗师运用干针疗法治疗疼痛性疾病取得了较好效果,同时干针疗法在世界范围得到了很好的宣传。而2015年下半年的"干针立法"事件将干针疗法与中医针灸之间的矛盾带入了公众视野。因此,笔者首先从干针历史、刺激部位及针刺手法3个方面与中医针灸进行比较,并结合文献证明干针是中医针灸疗法在西方的发展与创新。其次,笔者通过对干针立法事件的反思,总结了该事件对针灸国际化发展的启示。

Purpose: To validate and explore the application of a rat model of chronic constriction injury to the partial sciatic nerve in investigation of acupuncture analgesia.Methods: Chronic constriction injury of the sciatic nerve (CCI) and chronic constriction injury of the partial sciatic nerve (CCIp) models were generated by ligating either the sciatic nerve trunk or its branches in rats. Both models were evaluated via paw mechanical withdrawal latency (PMWL), paw mechanical withdrawal threshold (PMWT), nociceptive reflex-induced electromyogram (C-fiber reflex EMG), and dorsal root ganglion immunohistochemistry. Electroacupuncture (EA) was performed at GB30 to study the analgesic effects on neuropathic pain and the underlying mechanisms.Results: Following ligation of the common peroneal and tibial nerves, CCIp rats exhibited hindlimb dysfunction, hind paw shrinkage and lameness, mirroring those of CCI rats (generated by ligating the sciatic nerve trunk). Compared to presurgery measurements, CCIp and CCI modeling significantly decreased the PMWL and PMWT. EA at GB30 increased the PMWL and PMWT in both CCI and CCIp rats. Calcitonin gene-related polypeptide and substance P expressions were apparently increased in both CCI and CCIp groups, but were not different from each other. The C-fiber reflex EMG of the biceps femoris was preserved in CCIp rats, but it could not be recorded in CCI rats on the 5th day after nerve ligation. The C-fiber reflex EMG was reduced at 0, 1, and 2 minutes after EA in CCIp rats, but only at 0 and 1 minute after EA in normal rats.Conclusion: The CCIp model is better than the CCI model for studying acupuncture analgesia on chronic neuropathic pain and the underlying mechanisms.

疼痛性疾病是针刺治疗的优势病种,但近几年国外关于针刺镇痛临床研究的阴性结果报道,使得人们开始重新思考中、外针刺镇痛有效性结论的歧见。本文从1)咖啡因与疼痛的关系,2)腺苷及其受体与咖啡因,3)针刺镇痛与咖啡因等3个方面分析了咖啡因与中、外针刺镇痛效应差异的可能联系。动物实验结果表明,中等剂量咖啡因可以削弱针刺对小鼠足底切口痛模型的镇痛效应,而咖啡因在多种饮食物中存在,同时也是咖啡的主要成分。在西方,大约有85%以上的成年人有咖啡饮用习惯,因此,笔者旨在围绕咖啡因、腺苷及其受体、针刺镇痛3者之间的关系,探讨咖啡饮用习惯对针刺镇痛效应的可能影响,为分析中、外针刺镇痛效应的疗效差异提供一些思路。

Background: In Chinese medicine, dual effects on target organs are considered a primary characteristic of acupoint. Acupoints may be classified as heterotopic or homotopic in terms of spinal segmental innervation: homotopic acupoints contain afferent innervation in the same segment from which efferent fibers innervate target visceral organs, and heterotopic acupoints utilize different spinal segments to innervate target visceral organs than the segment receiving the afferent signal. It is well-known that dual effects of acupuncture on the bladder can be generated based on different states of the bladder, however, the dual effects of single acupoint stimulation and acupoint site-specificity (homotopic acupoints and heterotopic acupoints) on the bladder have yet to be investigated.Methods: Twenty Sprague-Dawley rats were anesthetized and the intravesical pressure was measured via a manometric balloon inserted into the bladder. The acupuncture needle was separately inserted to a depth of 4 mm at the acupoints RN1 (Huiyin), RN3 (Zhongji), BL28 (Pangguangshu), BL32 (Ciliao), RN2 (Qugu) or BL23 (Shenshu), and manually rotated right then left with a frequency of 2 Hz for 1 min. Following acupuncture stimulation, bladder pressure was recorded and compared against the pre-stimulation measurements.Results: During the bladder's active state, manual acupuncture (MA) at RN1, RN3, BL28, BL32 or RN2 inhibited bladder motility (P < 0.01). In the static bladder, MA at RN1, RN3, BL28, BL32, RN2 or BL23 increased bladder motility (P < 0.01).Conclusions: MA at homotopic acupoints may produce dual effects on bladder motility: inhibiting bladder motility when in an active state and enhancing bladder motility when in a static state.

BackgroundPrevious studies have demonstrated the efficacy of somatic stimulation for patients with gastrointestinal motility disorders. However, little effort has been made to investigate the effects of acupuncture on colonic motility, particularly in pathological conditions. The precise mechanism employed in the regulation of acupuncture on colonic motility still remains unclear.MethodsWe assessed the effect of acupuncture at heterotopic acupoints on distal colonic motility using a warm-water-filled manometric balloon inserted 5-6 cm into the rectum of anesthetized normal rats or rats with diarrhea or constipation. Choline chloride, 4-DAMP, cobra venom and capsaicin were separately applied to investigate the role of M-3 receptors in the regulation of distal colonic motility by acupuncture at heterotopic acupoints, and whether A- and/or C-fibers are required for triggering distal colonic motility by acupuncture.Key ResultsAcupuncture at heterotopic acupoints increased distal colonic motility not only in normal rats but also in rats with constipation or diarrhea. M-3 receptors play an important role in the facilitation of distal colonic motility triggered by acupuncture at heterotopic acupoints. Afferent nerve A- and C-fibers mediate the transduction of the acupuncture signal and C-fibers are essential for enhancing the effect of acupuncture at the heterotopic acupoint on distal colonic motility.Conclusions & InferencesOur results reveal that acupuncture at heterotopic acupoints increases distal colonic motility regardless of normal or pathological conditions via predominately activating C-fibers of somatic afferent nerve and M-3 receptors.