Chronic pain is a debilitating and rather common health problem. The present shortage in analgesic drugs with a favorable spectrum but without remarkable side effects furthered the search for alternative therapeutic manipulations. Increasing evidence from both basic and clinical research on acupuncture, a main alternative therapy of traditional Chinese medicine, suggests that chronic pain is sensitive to acupuncture procedures. Clarification of the underlying mechanisms is a challenge of great theoretical and practical significance. The seminal hypothesis of Geoffrey Burnstock and the astounding findings of Maiken Nedergaard on the involvement of purinergic signaling in the beneficial effects of acupuncture fertilized the field and led to an intensification of research on acupurines. In this review, we will summarize the state-of-the-art situation and try to forecast how the field is likely to develop in the future.

As part of traditional Chinese medicine, acupoints are considered a dynamic functional area, which can reflect the internal condition of the body. When the body is suffering from disease or injury, corresponding acupoints are believed to be activated and manifest in several sensitized forms, including expansion of the receptive field, pain sensitization, and heat sensitization. Such phenomena are believed to gradually disappear concomitantly with recovery from the disease. Acupoint states are therefore changeable according to health status, a phenomenon known as acupoint sensitization. This review aims to provide an overview of acupoint sensitization based on existing research results and determine priorities for future research. Systematic literature retrieval was conducted in Medline, Embase, Cochrane Library, CINAHL, and AMED from inception to 18 July 2018. Current evidence from research findings to date indicate that acupoint sensitization is based on neurogenic inflammation and that stimulation of sensitized acupoints presents a potential trend of generating a better clinical effect when compared with stimulation of unsensitized points.

Sleep contributes to the maintenance of overall health and well-being. There are a growing number of patients who have headache disorders that are significantly affected by poor sleep. This is a paradoxical relationship, whereby sleep deprivation or excess sleep leads to a worsening of headaches, yet sleep onset also alleviates ongoing headache pain. Currently, the mechanism of action remains controversial and poorly understood. The glymphatic system is a newly discovered perivascular network that encompasses the whole brain and is responsible for removing toxic proteins and waste metabolites from the brain as well as replenishing nutrition and energy. Recent studies have suggested that glymphatic dysfunction is a common underlying etiology of sleep disorders and headache pain. This study reviews the current literature on the relationship between the glymphatic system, sleep, and headaches, discusses their roles, and proposes acupuncture as a non-invasive way to focus on the glymphatic function to improve sleep quality and alleviate headache pain.

Purinergic signaling has recently been suggested to constitute the cellular mechanism underlying acupuncture-induced analgesia (AA). By extending the original hypothesis on endogenous opioids being released during AA, Geoffrey Burnstock and Maiken Nedergaard supplied evidence for the involvement of purinoceptors (P2 and P1/A1 receptors) in the beneficial effects of AA. In view of certain pain states (e.g. neuropathic pain) which respond only poorly to therapy with standard analgesics, as well as with respect to the numerous unwanted effects of opioids and non-steroidal anti-inflammatory drugs, it is of great significance to search for alternative therapeutic options. Because clinical studies on AA yielded sometimes heterogeneous results, it is of eminent importance to relay on experiments carried out on laboratory animals, by evaluating the data with stringent statistical methods including comparison with a sufficient number of control groups. In this review, we summarize the state of the art situation with respect to the participation of P2 receptors in AA and try to forecast how the field is likely to move forward in the future.

Ischemic stroke (IS) has been associated with an impairment in glymphatic function. Xuefu Zhuyu Decoction (XFZYD) is widely used in the prevention and treatment of ischemic stroke. We hypothesized that Xuefu Zhuyu decoction pretreatment could attenuate early neurological deficits after ischemic stroke by enhancing the function of the glymphatic system. To prove our hypothesis, we carried out temporary middle cerebral artery occlusion and reperfusion surgery on C57BL/6 mice and then measured neurological score, infarct size and performed hematoxylin-eosin staining to assess stroke outcomes after 24 h of reperfusion. Subsequently, we injected fluorescent tracers in to the cisterna magna and evaluated tracer distribution in coronal brain sections. The polarization of aquaporin-4 (AQP4), colocalization of aquaporin-4, α-dystroglycan, β-dystroglycan and agrin were determined by immunofluorescence. Our research showed that pretreatment with Xuefu Zhuyu decoction significantly alleviated neurological scores, neurological deficits and pathological abnormalities in a mouse model of ischemic stroke. Importantly, Xuefu Zhuyu decoction pretreatment enhanced cerebrospinal fluid influx, protected aquaporin-4 depolarization and promoted the colocalization of aquaporin-4 with its anchoring proteins in the brain. Our findings highlight novel mechanisms underlying the neuroprotective effect of Xuefu Zhuyu decoction pretreatment on ischemic stroke-induced brain damage through the glymphatic system. Xuefu Zhuyu decoction pretreatment may offer a promising approach to slow the onset and progression of ischemic stroke.