Electroacupuncture on the sciatic nerve innervated acupoint "Huan-Tiao" alleviates inflammatory pain in mice : involvement of peripheral and central adiponectin mechanisms

Abstract

The research of antinociceptive mechanisms of acupuncture never stopped in the last three decades, and gradually revealed that endogenous analgesic substances such as opioids, serotonin, norepinephrine, cannabinoid, corticosterone, and adenosine in the nervous system contribute to the efficacy of acupuncture analgesia. However, little know whether substances in the peripheral circulation also play a role in the analgesic process. Recently, adiponectin (APN) signaling showed to possess analgesic effects. APN is a circulating adipokine that is secreted specifically from the adipose tissue, released into the bloodstream, then entering the central nervous system (CNS) from the circulation. Two APN receptors, adipoR1 co-locates with astrocytes and microglia, and adipoR2 co-locates with neurons in the CNS to mediate the analgesic effects of APN. Adenosine monophosphate-activated protein kinase (AMPK) is a major downstream signaling molecule of APN. Activated AMPK co-locates with neurons in the spinal cord that has analgesic effects and inhibits central sensitization.

Besides, literatures had indicated electroacupuncture (EA) influences APN levels and AMPK activation in the CNS. However, there is no direct evidence indicating that the analgesic effects of EA depend on the involvement of APN and its receptor-mediated AMPK activation. Therefore, I hypothesized that the analgesic effects of EA stimuli on the sciatic nerve innervated acupoint “Huan-Tiao” require the involvement of APN and its receptors (adipoR1/2) to activate AMPK at the spinal level.

To examine the hypothesis, complete Freund’s adjuvant (CFA)-induced mouse model of inflammatory pain was used to explore the correlation between EA analgesia and APN signaling. EA, at 10 Hz, 2-2.5 mA, and 0.1 ms pulse width for 20 min, was administered to stimulate sciatic nerve through acupoint “Huan-Tiao”. Recombinant mouse APN, dicer-substrate siRNA (DsiRNA), AICAR or Compound C were delivered by intrathecal injection to examine the relationship between EA, APN, adipoR1/2 and AMPK. Paw withdraw threshold (PWT) and paw withdraw latency (PWL) were measured to determine the sensitivity of mechanical allodynia and thermal hyperalgesia.

During the examination of this hypothesis, I established the following major findings. (1) EA alleviates mechanical allodynia and thermal hyperalgesia and evokes increased APN expression in the spinal cord. (2) Intrathecal treatment with recombinant mouse APN has an analgesic effect. EA fails to suppress pain in mice lacking APN. (3) APN is coexpressed in blood vessels in the CNS. Furthermore, there exists a negative correlation between APN in the peripheral circulation and spinal cord. EA advances the appearance of this negative correlation. (4) AdipoR2, not adipoR1, mediates EA- and APN-produced analgesic effects at the spinal level. (5) The spinal activation of AMPK is required for the EA-APN-adipoR2 axis produced analgesic effects.

In conclusion, EA stimuli on the sciatic nerve inverted acupoint “Huan-Tiao” alleviated the sensitivity of mechanical allodynia and thermal hyperalgesia. APN and adipoR2-mediated activation of AMPK is involved in EA-produced analgesic effects. This reveals a new mechanism through which EA might promote APN in peripheral circulation to flow into the spinal cord, and then activate neuronal AMPK to inhibit central sensitization through adipoR2.