Electroacupuncture reduces chronic itch via cannabinoid CB1 receptors in the ventrolateral periaqueductal gray

Abstract

Chronic itch severely reduces the quality of life of patients. Electroacupuncture (EA) is widely used to treat chronic itch. However, the underlying mechanism of this therapeutic action of EA is largely unknown. Cannabinoid CB1 receptors in the ventrolateral periaqueductal gray (vlPAG) mediate the analgesic effect of EA. Using a dry skin-induced itch model in mice, we determined whether EA treatment reduces chronic itch via CB1 receptors in the vlPAG. We showed that the optimal inhibitory effect of EA on chronic itch was achieved at the high frequency and high intensity (100 Hz and 3 mA) at “Quchi” (LI11) and “Hegu” (LI14) acupoints, which are located in the same spinal dermatome as the cervical skin lesions. EA reversed the increased expression of CB1 receptors in the vlPAG and decreased the concentration of 5-hydroxytryptamine (5-HT) in the medulla oblongata and the expression of gastrin-releasing peptide receptors (GRPR) in the cervical spinal cord. Furthermore, knockout of CB1 receptors on GABAergic neurons in the vlPAG attenuated scratching behavior and the 5-HT concentration in the medulla oblongata. In contrast, knockout of CB1 receptors on glutamatergic neurons in the vlPAG blocked the antipruritic effects of EA and the inhibitory effect of EA on the 5-HT concentration in the medulla oblongata. Our findings suggest that EA treatment reduces chronic itch by activation of CB1 receptors on glutamatergic neurons and inhibition of CB1 receptors on GABAergic neurons in the vlPAG, thereby inhibiting the 5-HT release from the medulla oblongata to GRPR-expressing neurons in the spinal cord. Our findings suggest that EA attenuates chronic itch via activating CB1 receptors expressed on glutamatergic neurons and downregulating CB1 receptors on GABAergic neurons in the vlPAG, leading to the reduction in 5-HT release in the rostroventral medulla and GRPR signaling in the spinal cord. Our study not only advances our understanding of the mechanisms of the therapeutic effect of EA on chronic itch but also guides the selection of optimal parameters and acupoints of EA for treating chronic itch.

Role of GRPR in Acupuncture Intervention in the “Itch-scratch Vicious Cycle” Spinal Circuit of Chronic Pruritus

“…Substance P(SP) [27,31], 5-HT [28], 5-HT receptor [28], IL-4 [32], Interferon-gamma (IFN-γ) [32], histamine [34], Prostaglandin E 2 (PGE 2 ) [34], ionized calcium-binding adapter molecule 1(Iba1) [43] TNF-α [43], IgE [44], IL-1 [42], IL-6 [42], IL-12 [42], IL-10 [42], Tumor necrosis factor-α (TNF-α) [42,43], Serum corticosterone [39] Scratch behavioral tests [27,28,31,34], general state, depressive-like behaviors test (open field test, sugar water consumption test, food consumption measurement, and body mass change measurement) [27], lesion, pathomorphological, thickness and dermatitis of skin [27,31], weight measurement [31] Immunofluorescence Beta-endorphinergic (β-EP) neurons [29], 5-HT neurons [30], cannabinoid receptors type 1 (CB1) receptors [40], 5-HT neurons [40], GRPR neurons [40], Dynorphin (DYN)-A [41] Scratch behavioral tests [30,40,41] Immunohistochemistry (IHC) IL-4 [38], IFN-γ [38], Scar tissues [44] Behavioral tests (including scratch) [38], skin thickness, and dermatitis scores were obtained [44] Western-blot(WB) Beta-endorphinergic [29], 5-HT 2B receptor protein…”

“…One hundred and sixteen studies were excluded after reading the full text. Finally, 19 animal studies (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) were included. The specific study screening process and results are shown in Fig.…”

“…Through optogenetic manipulation and conditioned place preference or conditioned place aversion experiments, two types of neurons in the VTA brain region were confirmed to regulate two different components of itch perception, glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurons that mediate the aversion induced by pruritogenic agents and dopaminergic neurons that mediate the pleasure the following scratching. Finally, VTA neurons were found Table 3 Brain regions closely related to itching and scratching circulation References Brain regions [39] Nucleus accumbens, dorsolateral striatum, ventral tegmental area [40] Ventrolateral periaqueductal gray (vlPAG) [71] Anterior cingulate cortex-dorsomedial striatum (ACC-DMS) [72] Supplementary motor area (SMA), premotor cortex (PM), the primary motor cortex (PMC), middle cingulate cortex (MC), caudate nucleus (CN) [67] Insula, cingulate cortices, basal ganglia, frontoparietal control network (superior parietal lobule and dorsolateral prefrontal cortex) [68] Anterior cingulate, insula, claustrum, hippocampus, nucleus accumbens [70] Dorsolateral prefrontal cortex (dlPFC), cerebellum [73] ACC、posterior cingulate cortex(PCC), retro splenial cingulate cortex, dlPFC, caudate nucleus, putamen, PMC, primary somatosensory cortex, superior parietal lobe [6] Ventral tegmental area (VTA) [74] ACC, insula, VTA, periaqueductal gray matter (PAG), basal ganglia Fig. 2 Itch provoking scratching caused pain and pruritus will be together transmitted to the center.…”

Neural circuit mechanisms of acupuncture effect: where are we now?

“…Moreover, electroacupuncture treatment for chronic itch may be associated with the expression of CB1 receptors in the descending inhibitory system. High-frequency and high-intensity electroacupuncture reduce the expression of CB1 receptors in GABAergic neurons of the ventrolateral periaqueductal gray (vlPAG), inhibit serotonin (5-HT) levels in the spinal cord, and thereby alleviate chronic itch ( 114 ). Additionally, the mesolimbic reward system circuitry not only participates in acupuncture analgesia and addiction treatment but has also been found to play a role in acupuncture treatment for comorbid anxiety and depression and sleep disorders.…”