Abstract
Although acupuncture analgesia has been reported in clinical trials, its mechanisms have been unclear. It was recently reported that spinal astrocytes-produced interleukin-17A (IL-17A) facilitates inflammatory pain. Hypothesizing that electroacupuncture (EA) would suppress inflammation-enhanced IL-17A synthesis to inhibit pain, we induced hyperalgesia, as measured by decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, by subcutaneously injecting complete Freund's adjuvant (CFA, 0.08 ml, 40 μg Mycobacterium tuberculosis) into the hind paws of rats, or intrathecal (i.t.) IL-17A (400 ng in 10 μl) into the lumbar spinal cord. We then gave EA at acupoint GB30 for two 20-min periods, once immediately after CFA or IL-17A administration and again 2 h post-injection. For sham control, EA needles were inserted into GB30 without stimulation. PWL was measured before and 2.5 and 24 h after injection. Spinal IL-17A, IL-17 receptor A (IL-17RA), and phosphorylated NR1, an essential subunit of the N-methyl D-aspartate receptor (NMDAR), were determined 24 h post-CFA or –IL-17A using immunohistochemistry and western blot. Compared to sham control, EA inhibited CFA-caused thermal hyperalgesia 2.5 and 24 h post-CFA and concurrently suppressed inflammation-enhanced IL-17A and IL-17RA synthesis and NR1 phosphorylation in the ipsilateral spinal cord. EA inhibited IL-17A-produced thermal hyperalgesia, IL-17RA synthesis and NR1 phosphorylation. Our data suggest that EA inhibits inflammatory pain by blocking spinal IL-17A synthesis. Since previous study shows that IL-17A is located in astrocytes and IL-17RA and NR1 are in neurons, the data suggest that EA alleviates pain by modulating glia-neuronal interactions that involve IL-17A, IL-17RA, and NR1 phosphorylation.
Highlights
Spinal glia is known to be involved in transmission and modulation of noxious messages
It is reported that IL-1β is up-regulated in spinal astrocytes to increase NMDA NR1 phosphorylation, an essential subunit of the N-methyl Daspartate receptor (NMDAR), which in turn promote pain in an inflammatory pain rat model [3,4,5,6]
Opioid receptors are found in astrocytes [28], which suggests that opioids act directly on astrocytes to inhibit IL-17A synthesis
Summary
Spinal glia is known to be involved in transmission and modulation of noxious messages. Intrathecal (i.t.) injection of IL-17A in rats induced thermal hyperalgesia and peripheral inflammation caused up-regulation of IL-17A in spinal astrocytes and IL-17 receptor A (IL-17RA) in spinal neurons [9] These studies indicate that spinal IL-17A facilitates pain. Previous study shows that electroacupuncture (EA) significantly increases paw withdrawal latency (PWL) and inhibits intra-plantar CFA-induced up-regulation of glial fibrillary acidic protein, a marker of astrocytes [12]. The rats in experiments 1 were tested for hind paw withdrawal latency (PWL) by a previously described method [16, 17] They were acclimatized for 30 min under an inverted clear plastic box on the glass surface of a Paw Thermal Stimulator System (UCSD, San Diego, USA).
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