From Peripheral to Central: The Role of ERK Signaling Pathway in Acupuncture Analgesia

Pain significantly interferes with quality of life and functioning.61 Diverse pharmacologic treatments3,49 and analgesic injections24,31 are used to relieve pain. Patients, however, often seek alternatives because of unsatisfactory results or side effects of the conventional approaches.49,53 Acupuncture has gained recognition as a modality for pain treatment.51,63 Accumulated evidence supports the clinical effectiveness of acupuncture to treat knee osteoarthritis,46 headaches,65 and low back pain.4,58 Despite substantial research endeavors on the analgesic mechanisms of acupuncture,18,29,44 various mechanisms related to acupuncture needling and its effects remain largely vague. It has been recognized that understanding the molecular and cellular mechanisms of nociception is important for the treatment of pain,62 which may also provide insight into the therapeutic value of acupuncture and pave the way for the development of mechanism-based therapeutic strategies for pain management.39 Some have speculated that the changes involved in the local manipulation of acupuncture needles play a crucial role in triggering the clinical effects of acupuncture, including pain alleviation.28,33,39,64 Intriguingly, Goldman and his colleagues recently reported that acupuncture needling induces an increase in adenine nucleotides (adenosine triphosphate [ATP], adenosine diphosphate [ADP], and adenosine monophosphate [AMP]) and adenosine in the muscle and that the adenosine A1 receptor is necessary for the local antinociceptive action of acupuncture to function.19 Langevin et al suggested that acupuncture-induced morphologic changes in the subcutaneous loose connective tissue and fibroblasts play crucial roles in cytoskeletal remodeling,36,37 whereas the relationship between the connective tissue changes and the therapeutic effects remain unrevealed. Although previous studies have provided important information about the local changes around acupuncture points,1,19,26,56 few studies have investigated the local molecular and cellular mechanisms that are responsible for the analgesic effects of acupuncture. Therefore, we hypothesized that molecular signaling around the needled acupuncture point is an essential part of the clinical effect of acupuncture. To test this hypothesis, the aims of this study were 1) to identify molecular entities following acupuncture needling at the local skin level and 2) to investigate the role of such identified molecules on the analgesic effects of acupuncture. To our knowledge, this is the first study to report molecular changes related to acupuncture needling and to suggest that they are biochemical hallmarks that initiate the effects of acupuncture, including analgesic effects.