Transient receptor potential vanilloid 1 (TRPV1) has been implicated in peripheral inflammation and is a mediator of the inflammatory response to various noxious stimuli. However, the interaction between TRPV1 and N-methyl-D-aspartate (NMDA) receptors in the regulation of inflammatory pain remains poorly understood. This study aimed to investigate the analgesic effects of intrathecal administration of capsazepine, a TRPV1 antagonist, on carrageenan-induced inflammatory pain in mice and to identify its interactions with NMDA receptors. Inflammatory pain was induced by intraplantar injection of 2% carrageenan in male ICR mice. To investigate the analgesic effects of capsazepine, pain-related behaviors were evaluated using von Frey filaments and a thermal stimulator placed on the hind paw. TRPV1 expression and NMDA receptor phosphorylation in the spinal cord and glutamate concentration in the spinal cord and serum were measured. Intrathecal treatment with capsazepine significantly attenuated carrageenan-induced mechanical allodynia and thermal hyperalgesia. Moreover, carrageenan-enhanced glutamate and phosphorylation of NMDA receptor subunit 2B in the spinal cord were suppressed by capsazepine administration. These results indicate that TRPV1 and NMDA receptors in the spinal cord are associated with inflammatory pain transmission, and inhibition of TRPV1 may reduce inflammatory pain via NMDA receptors.

The Shenmen point (acupuncture point heart 7: HT7), located in the heart meridian, is frequently used to treat mental disorders, including drug addiction, anxiety, and depression. This study aimed to determine how HT7 regulates anxiety and negative emotions caused by repeated alcohol administration, focusing on the amygdala and paraventricular nucleus (PVN). Repeated administration of alcohol (ETOH; 2 g/kg, i.p. injection, 16% v/v) for 14 days increased the corticosterone (CORT) levels, and HT7 stimulation reduced the plasma CORT levels. HT7 stimulation mitigated anxiety-like behaviors and reduced 22-kHz ultrasonic vocalizations in rats receiving repeated ETOH injections. HT7 stimulation increased the amygdala expression of mature brain-derived neurotropic factor (mBDNF) and phosphorylated tropomyosin receptor kinase B (pTrkB) and decreased the PVN corticotropin-releasing hormone (CRH) expression. Amygdala microinjections of the TrkB antagonist ANA-12 (0.1 pmol/1 μL) reversed the increase in PVN CRH levels. The reduced PVN CRH levels were regulated by CRH-expressing neurons in the amygdala, and the increased amygdala CRH levels were affected by the HT7-stimulation induced increases in mBDNF. HT7 stimulation alleviates increased stress hormone levels and mitigates anxiety and negative emotions caused by repeated ETOH administration. These results provide scientific support for the clinical use of acupuncture to treat various alcoholism-induced diseases.

Docetaxel, a chemotherapeutic agent used to treat breast cancer, produces a robust painful neuropathy that is aggravated by mechanical and thermal stimuli. This study was undertaken to investigate the analgesic effects of electrical stimulation on docetaxel-induced neuropathic pain in mice and to identify associated changes in ultrasound vocalizations. Peripheral neuropathy was induced with intraperitoneally injected docetaxel (5 mg/kg) on 3 times every 2 days in male ICR mice. Electrical wrist stimulation was administered and pain behavior signs were evaluated by von Frey filaments and thermal stimulation on the hind paw. Ultrasound vocalizations were measured using ultrasound microphones, after electrical stimulation. After mice developed docetaxel-induced neuropathic pain behavior, an electrical stimulation temporarily attenuated mechanical allodynia and thermal hyperalgesia. In formalin and NMDA test, pain-induced mice showed increases in 10-30 kHz ultrasound vocalizations, but not in 30-50 and 50-80 kHz vocalizations. Treatment with docetaxel selectively increased 10-30 kHz ultrasound vocalizations, whereas electrical stimulation caused a meaningful decrease. Moreover, electrical stimulation suppressed the docetaxel-enhanced phosphorylation of the NMDA receptor NR2B subunit in the spinal dorsal horn. These results of the analgesic effect of electrical stimulation in chemotherapy-induced neuropathy could potentially provide a new method to treat and manage peripheral neuropathy in patients with cancer.

Most ETOH addiction preclinical studies have focused on the rewards of chronic ETOH self-administration or the ETOH reinstatement model. Acute ETOH administration studies are scarce despite the potential of ETOH to cause sedation, intoxication and reduced acute functional tolerance. Here, we established a rat model of acute ETOH administration induced by an intraperitoneal injection of 1 g/kg ethanol and assessed the similarities in physiological and behavioral effects between acupuncture and Sigma1 R antagonists. Male Wistar rats (300−330 g) received pretreatment with (1) saline injection, (2) saline + mechanical stimulation using a mechanical acupuncture instrument (MAI) for acupuncture at the Shenmen (HT7), (3) ETOH (1 g/kg) injection, (4) ETOH + HT7, or (5) the selective σ1 R antagonist BD 1047 (3, 10, or 30 mg/kg, intraperitoneal (IP) injection). ETOH (1 g/kg) or saline was IP injected after 10 min. Then, ETOH-induced immobility was evaluated in an open field arena, ultrasonic vocalizations (USVs) indicating ethanol-induced emotional changes were recorded in a recording chamber, and the rats were sacrificed for the analysis of protein levels of σ1 R in several regions of the brain. Acute ethanol exposure increased the immobile time, 22-kHz USVs, and protein levels of σ1 R in the ventral tegmental area (VTA). However, pretreatment with acupuncture at HT7 induced recovery of immobile time, reduced 22-kHz USVs, and regulated the protein levels of σ1 R in the VTA. These effects have similarities with IP injection of BD 1047 (10 mg/kg). This study showed that acupuncture at HT7 regulates immobility and 22-kHz USVs via Sigma1 R in the VTA upon acute ETOH exposure.

We recently developed a mechanical acupuncture instrument (MAI) that applies mechanical stimulation to acupuncture points in effectively treating hypertension and addiction in animal models. However, its analgesic effect on inflammatory pain remains unclear. Here, we aimed to determine the optimal duration of MAI treatment at any given acupuncture point to improve analgesic effects. Adult male ICR mice (20–25 g, 6 weeks old, n = 6 per group) were used to evaluate whether MAI administration or TRPV1 (transient receptor potential vanilloid 1) inhibition had analgesic effects. Then, we investigated whether it affected TRPV1 expression and glial cells in the spinal cord of mice. The capsaicin test was used to identify the most effective acupoints and optimal treatment times for MAI. Additionally, we induced inflammatory pain in mice by administering a 2% carrageenan via intraplantar injection. To assess the analgesic effects of MAI treatment and TRPV1 inhibition, we evaluated pain-related behavior using von Frey filaments and a thermal stimulator applied to the hind paw. MAI treatment significantly suppressed pain-related behaviors. In particular, paw-licking duration was markedly reduced in the group treated with MAI for 60 s at ST36 compared to the capsaicin-treated group (p < 0.05), suggesting a robust analgesic effect. Additionally, MAI and capsazepine administration significantly attenuated carrageenan-induced mechanical allodynia and thermal hyperalgesia compared to the carrageenan-only group (p < 0.05 to p < 0.001). Additionally, MAI treatment and capsazepine administration effectively suppressed the carrageenan-induced upregulation of TRPV1 and glial cells in the spinal cord. In conclusion, our findings show that MAI administration at ST36 significantly alleviated inflammatory pain and was associated with downregulation of TRPV1 expression and microglial activation in the spinal cord. The present findings suggest that TRPV1 signaling is involved in the analgesic effects of mechanical acupuncture; however, a direct causal relationship has yet to be established.

Drug addiction has become a worldwide problem, affecting millions of people across the globe. While the majority of mechanistic studies on drug addiction have been focused on the central nervous system, including the mesolimbic dopamine system, the peripheral actions of drugs of abuse remain largely unknown. Our preliminary study found that the systemic injection of cocaine increased peripheral skin temperature. This led us to our present study, which investigated the mechanisms underlying the increase in peripheral temperature following cocaine injection. Male Sprague Dawley rats were anesthetized with pentobarbital sodium, and peripheral skin temperature measurements were taken using a thermocouple needle microprobe and an infrared thermal camera. Cocaine injection caused an acute rise in peripheral body temperature, but not core body temperature, about 10 min after injection, and the temperature increases were occluded by systemic injection of dopamine D2 receptor antagonist L741,626, but not D1 receptor antagonist SCH23390. In addition, systemic administration of bromocriptine, a dopamine D2 receptor agonist, significantly increased peripheral temperature. Infrared thermal imaging showed that the thermal increases following cocaine injection were predominantly in the distal areas of the forelimbs and hindlimbs, relative to core body temperature. Treatment with cocaine or bromocriptine decreased the size of skin blood vessels without affecting the expression of dopamine D2 receptors. These results suggest that increased peripheral temperature in skin following cocaine injection is associated with the activation of the dopamine D2 receptor.