Electroacupuncture attenuates surgical pain-induced delirium-like behavior in mice via remodeling gut microbiota and dendritic spine.

Surgical pain is associated with delirium in patients, and acupuncture can treat pain. However, whether electroacupuncture can attenuate the surgical pain-associated delirium via the gut-brain axis remains unknown. Leveraging a mouse model of foot incision-induced surgical pain and delirium-like behavior, we found that electroacupuncture stimulation at specific acupoints (e.g., DU20+KI1) attenuated both surgical pain and delirium-like behavior in mice. Mechanistically, mice with incision-induced surgical pain and delirium-like behavior showed gut microbiota imbalance, microglia activation in the spinal cord, somatosensory cortex, and hippocampus, as well as an enhanced dendritic spine elimination in cortex revealed by two-photon imaging. The electroacupuncture regimen that alleviated surgical pain and delirium-like behavior in mice also effectively restored the gut microbiota balance, prevented the microglia activation, and reversed the dendritic spine elimination. These data demonstrated a potentially important gut-brain interactive mechanism underlying the surgical pain-induced delirium in mice. Pending further studies, these findings revealed a possible therapeutic approach in preventing and/or treating postoperative delirium by using perioperative electroacupuncture stimulation in patients.

Comparison between acupuncture therapy and gabapentin for chronic pain: a pilot study.

BACKGROUND: We examined whether the effect of true electroacupuncture on pain and functionality in chronic pain participants can be differentiated from that of medication (gabapentin) by analyzing quantitative sensory testing (QST). METHODS: We recruited chronic back and neck pain participants who received six sessions (twice weekly) of true electroacupuncture versus sham electroacupuncture or 3 weeks of gabapentin versus placebo treatment. QST profiles, pain scores, and functionality profile were obtained at baseline (visit 1) and after three sessions (visit 4) or six sessions (visit 7) of acupuncture or 3 weeks of gabapentin or placebo. RESULTS: A total of 50 participants were analyzed. We found no differences in QST profile changes (p = 0.892), pain reduction (p = 0.222), or functionality (p = 0.254) between the four groups. A major limitation of this pilot study was the limited number of study participants in each group. CONCLUSION: This pilot study suggests that a large-scale clinical study with an adequate sample size would be warranted to compare acupuncture and medication therapy for chronic pain management. TRIAL REGISTRATION NUMBER: NCT01678586 (ClinicalTrials.gov).

A randomized trial to assess the immediate impact of acupuncture on quantitative sensory testing, pain, and functional status.

In this randomized clinical trial, we examined whether the effect of true acupuncture can be differentiated from sham acupuncture (pain and functionality) by analyzing quantitative sensory testing (QST) profiles in chronic pain participants. We recruited 254 healthy or chronic back and neck pain participants. Healthy subjects were included to control for a possible effect of acupuncture on baseline QST changes. Study participants received 6 sessions (twice weekly) of true acupuncture, sham acupuncture, or no acupuncture treatment (routine care). Quantitative sensory testing profiles, pain scores, and functionality profile were obtained at baseline (visit 1) and after 3 (visit 4) or 6 sessions (visit 7). A total of 204 participants were analyzed. We found no QST profile changes among 3 groups (P = 0.533 and P = 0.549, likelihood ratio tests) in either healthy or chronic pain participants. In chronic back and neck pain participants, true acupuncture reduced pain (visit 4: difference in mean [DIM] = -0.8, 95% confidence interval [CI]: -1.4 to -0.1, adjusted P = 0.168; visit 7: DIM = -1.0, 95% CI: -1.7 to -0.3, adjusted P = 0.021) and improved functional status including physical functioning (DIM = 14.21, 95% CI: 5.84-22.58, adjusted P = 0.003) and energy/fatigue (DIM = 12.28, 95% CI: 3.46-21.11, adjusted P = 0.021) as compared to routine care. Our results indicate that QST was not helpful to differentiate between true acupuncture and sham acupuncture (primary outcome) in this study, although true acupuncture reduced pain and improved functionality (secondary outcomes) when compared with routine care.

Alleviation of trigeminal neuropathic pain by electroacupuncture: the role of hyperpolarization-activated cyclic nucleotide-gated channel protein expression in the Gasserian ganglion.

INTRODUCTION: The aim of this study was to examine the effect of electroacupuncture (EA) on trigeminal neuropathic pain in rats and explore the potential mechanism underlying the putative therapeutic effect of EA. METHODS: Trigeminal neuropathic pain behavior was induced in rats by unilateral chronic constriction injury of the distal infraorbital nerve (dIoN-CCI). EA was administered at ST2 (Sibai) and Jiachengjiang. A total of 60 Sprague Dawley rats were divided into the following four groups (n = 15 per group) to examine the behavioral outcomes after surgery and/or EA treatment: sham (no ligation); dIoN-CCI (received isoflurane only, without EA treatment); dIoN-CCI+EA-7d (received EA treatment for 7 days); and dIoN-CCI+EA-14d (received EA treatment for 14 days). Both evoked and spontaneous nociceptive behaviors were measured. Of these, 12 rats (n = 4 from sham, dIoN-CCI, and dIoN-CCI+EA-14d groups, respectively) were used to analyze protein expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in the Gasserian ganglion (GG) by immunohistochemistry. RESULTS: dIoN-CCI rats exhibited mechanical allodynia and increased face-grooming activity that lasted at least 35 days. EA treatment reduced mechanical allodynia and face-grooming in dIoN-CCI rats. Overall, 14 days of EA treatment produced a prolonged anti-nociceptive effect as compared to 7-day EA treatment. The counts of HCN1 and HCN2 immunopositive puncta were increased in the ipsilateral GG in dIoN-CCI rats and were reduced by 14 days of EA treatment. DISCUSSION: EA treatment relieved trigeminal neuropathic pain in dIoN-CCI rats, and this effect was dependent on the duration of EA treatment. The downregulation of HCN expression may contribute to the anti-nociceptive effect of EA in this rat model of trigeminal neuropathic pain.

Ultrasmall Superparamagnetic Iron Oxide Imaging Identifies Tissue and Nerve Inflammation in Pain Conditions.

Objective: Correlation between radiologic structural abnormalities and clinical symptoms in low back pain patients is poor. There is an unmet clinical need to image inflammation in pain conditions to aid diagnosis and guide treatment. Ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle, is clinically used to treat iron deficiency anemia and showed promise in imaging tissue inflammation in human. We explored whether ferumoxytol can be used to identify tissue and nerve inflammation in pain conditions in animals and humans. Methods: Complete Freud's adjuvant (CFA) or saline was injected into mice hind paws to establish an inflammatory pain model. Ferumoxytol (20 mg/kg) was injected intravenously. Magnetic resonance imaging (MRI) was performed prior to injection and 72 hours postinjection. The changes in the transverse relaxation time (T2) before and after ferumoxytol injection were compared between mice that received CFA vs saline injection. In the human study, we administered ferumoxytol (4 mg/kg) to a human subject with clinical symptoms of lumbar radiculopathy and compared the patient with a healthy subject. Results: Mice that received CFA exhibited tissue inflammation and pain behaviors. The changes in T2 before and after ferumoxytol injection were significantly higher in mice that received CFA vs saline (20.8 ± 3.6 vs 2.2 ± 2.5, P = 0.005). In the human study, ferumoxytol-enhanced MRI identified the nerve root corresponding to the patient's symptoms, but the nerve root was not impinged by structural abnormalities, suggesting the potential superiority of this approach over conventional structural imaging techniques. Conclusions: Ferumoxytol-enhanced MRI can identify tissue and nerve inflammation and may provide a promising diagnostic tool in assessing pain conditions in humans.

Inhibition of HCN channel activity in the thalamus attenuates chronic pain in rats.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability in both peripheral and central nerve systems. Emerging evidence indicates that HCN channels are involved in the development and maintenance of chronic pain. However, the impact of HCN channel activity in the thalamus on chronic pain has not been examined. In this report, we evaluated the effect on nociceptive behaviors after infusion of a HCN channel blocker ZD7288 into the ventral posterolateral (VPL) nucleus of the thalamus in rats with neuropathic pain or monoarthritis. We show that ZD7288 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in rats with chronic pain. In the thalamus, immunoreactivity of both HCN1 and HCN2 subunits was increased in both rat models. These results suggest that the increased HCN channel activity in the thalamus of the ascending nociceptive pathway contributes to both chronic neuropathic and inflammatory pain conditions.

Noninvasive delivery of gene targeting probes to live brains for transcription MRI.

We aimed to test the feasibility of detecting gliosis in living brains when the blood-brain barrier (BBB) is disrupted. We designed a novel magnetic resonance (MR) probe that contains superparamagnetic iron oxide nanoparticles (SPION, a T2 susceptibility contrast agent) linked to a short DNA sequence complementary to the cerebral mRNA of glial fibrillary acidic protein (GFAP) found in glia and astrocytes. As a control, we also used a sequence complementary to the mRNA of beta-actin. Our objectives are to demonstrate that this new probe, SPION-gfap, could be delivered to the brain when administered by eyedrop solution to the conjunctival sac. We induced BBB leakage by puncture wound, global cerebral ischemia, and cortical spreading depression in C57BL6 mice; 1 day after probe delivery we acquired T2* MR images and R2* (R2* = 1/T2*) maps using a transcription MRI technique in live mice. We found that the SPION-gfap probe reported foci with elevated signal in subtraction R2* maps and that these foci matched areas identified as having extensive glial network (gliosis) in postmortem immunohistochemistry. Similarly, animals administered the control probe exhibited foci of R2* elevation that matched beta-actin-expressing endothelia in the vascular wall. We conclude that our modular MR probe, delivered in an eyedrop solution, effectively reports gliosis associated with acute neurological disorders in living animals. As BBB leakage is often observed in acute neurological disorders, this study also served to validate noninvasive delivery of MR probes to the brains of live animals after acute neurological disorders.

A stomatin-like protein encoded by the slp gene of Rhizobium etli is required for nodulation competitiveness on the common bean.

Rhizobium etli strain TAL182 is a competitive strain for effective nodulation of beans. From this strain, a novel gene was isolated, slp, which is 669 bp in size and required for nodulation competition on the common bean. The slp knockout mutant of TAL182 is defective in nodulation competition, shows reduced growth in the presence of 200 mM NaCl, KCl or LiCl and is complemented by the cloned slp gene. The deduced amino acid sequence of slp shows 66-72% similarity to stomatin proteins of Homo sapiens, Mus musculus and Caenorhabditis elegans. Expression of slp in Escherichia coli from a T7 promoter shows a 26 kDa protein which cross-reacts with human-stomatin-specific polyclonal antibody. Like the human stomatin protein, the slp-deduced protein, Slp, is very hydrophilic except for a single hydrophobic membrane-spanning domain. Among various bean-nodulating rhizobia, slp is present in R. etli, Rhizobium leguminosarum bv. phaseoli and Rhizobium tropici type A strains but is absent in R. tropici type B strains. It is also absent in Bradyrhizobium and several other Rhizobium spp.