Bee venom injection significantly reduces nociceptive behavior in the mouse formalin test via capsaicin-insensitive afferents.

UNLABELLED: Peripheral bee venom (BV) administration produces 2 contrasting effects, nociception and antinociception. This study was designed to evaluate whether the initial nociceptive effect induced by BV injection into the Zusanli acupoint is involved in producing the more prolonged antinociceptive effect observed in the mouse formalin test, and whether capsaicin-sensitive primary afferents are involved in these effects. BV injection into the Zusanli point increased spinal Fos expression but not spontaneous nociceptive behavior. BV pretreatment 10 minutes before intraplantar formalin injection dose-dependently attenuated nociceptive behavior associated with the second phase of the formalin test. The destruction of capsaicin-sensitive primary afferents by resiniferatoxin (RTX) pretreatment selectively decreased BV-induced spinal Fos expression but did not affect BV-induced antinociception. Furthermore, BV injection increased Fos expression in tyrosine hydroxylase immunoreactive neurons in the locus caeruleus, and this expression was unaltered by RTX pretreatment. Finally, BV's antinociception was blocked by intrathecal injection of 10 microg idazoxan, and this effect was not modified by RTX pretreatment. These findings suggest that subcutaneous BV stimulation of the Zusanli point activates central catecholaminergic neurons via capsaicin-insensitive afferent fibers without induction of nociceptive behavior. This in turn leads to the activation of spinal alpha2-adrenoceptors, which ultimately reduces formalin-evoked nociceptive behaviors. PERSPECTIVE: This study demonstrates that BV acupuncture produces a significant antinociception without nociceptive behavior in rodents, which is mediated by capsaicin-insensitive afferents and involves activation of central adrenergic circuits. These results further suggest that BV stimulation into this acupuncture point might be a valuable alternative to traditional electrical or mechanical acupoint stimulation.

Substantial role of locus coeruleus-noradrenergic activation and capsaicin-insensitive primary afferent fibers in bee venom's anti-inflammatory effect.

Several lines of evidence indicate significant interactions between the immune and nervous systems. Our recent study reveals that 'bee venom (BV) induced anti-inflammatory effect' (BVAI) was produced by sympathetic preganglionic neuronal activation and subsequent adrenomedullary catecholamine release in a zymosan-induced inflammation model. However, the specific peripheral input and the supraspinal neuronal systems that are involved in this BVAI remain to be defined. Here we show that subcutaneous BV injection into left hind limb significantly reduces zymosan-induced leukocyte migration and that this effect is completely inhibited by denervation of the left sciatic nerve. This BVAI was not affected by the destruction of capsaicin-sensitive primary afferent fibers using either neonatal capsaicin or resiniferatoxin (RTX) pretreatment. BV injection into the left hind limb significantly increased Fos expression in the contralateral locus coeruleus (LC) in non-inflamed mice. In zymosan-inflamed mice, BV injection produced a further increase in LC Fos expression as compared with non-inflamed mice. This BV-induced Fos increase in the LC was not affected by RTX pretreatment. Pharmacological blockage of central noradrenergic activity by either central chemical sympathectomy (i.c.v. 6-hydroxydopamine) or alpha2 adrenoceptor antagonism (i.c.v. idazoxan) completely blocked BVAI. Taken together, these results suggest that BVAI is mediated by peripheral activation of capsaicin-insensitive primary afferent fibers and subsequent central noradrenergic activation including the LC.

The anti-inflammatory effects of low- and high-frequency electroacupuncture are mediated by peripheral opioids in a mouse air pouch inflammation model.

BACKGROUND: Although acupuncture has been widely used for complementary therapeutic approaches to treat inflammatory diseases and inflammation-induced pain, the potential anti-inflammatory effects of acupuncture treatment remain controversial in clinical trials, and the underlying mechanisms are still unclear. OBJECTIVE: The objective was to determine whether electroacupuncture (EA) is able to suppress the peripheral inflammatory response (e.g., zymosan-induced leukocyte migration into air pouch). As part of a mechanistic approach, it was further evaluated whether endogenous opioid systems are involved in the "EA-induced anti-inflammatory effect" (EA-AI). METHODS: EA (1 or 120 Hz) was performed bilaterally in the Zusanli acupoint (ST36) or in a nonacupoint (gluteal muscle) for 30 min in ICR mice under anesthetic condition. The number of leukocytes that migrated into the air pouch was counted 4 hours after zymosan injection. EA was performed at 0, 0.5, 1, or 2 hours prior to zymosan injection, respectively. To evaluate opioid involvement in EA-AI, intrathecal naloxone (36 microg/mouse) and intraperitoneal naloxone methiodide (30 mg/kg) were administered 10 min before EA stimulation. RESULTS: Both the 1 and 120 Hz frequencies of EA into Zusanli acupoint at the same time with zymosan injection significantly reduced leukocyte migration into the air pouch as compared with those of control groups (i.e., anesthetic control and needling control into Zusanli acupoint without electrical stimulation). The EA stimulation into nonacupoint did not produce any significant anti-inflammatory effect. EA treatment at 0.5 hours prior to zymosan injection also produced an anti-inflammatory effect but 1 and 2 hours prior to zymosan injection did not elicit any effect. Peripheral opioid blockage significantly reversed EA-AI, whereas spinal opioid blockage did not alter EA-AI. CONCLUSION: EA can suppress peripheral inflammation through a peripheral opioid mechanism. To achieve the full effectiveness of EA, repeated application is recommended for the treatment of a variety of inflammatory diseases.

Acupoint stimulation with diluted bee venom (apipuncture) alleviates thermal hyperalgesia in a rodent neuropathic pain model: involvement of spinal alpha 2-adrenoceptors.

UNLABELLED: Chemical acupuncture with diluted bee venom (DBV), termed apipuncture, has been traditionally used in oriental medicine to treat several inflammatory diseases and chronic pain conditions. In the present study we investigated the potential antihyperalgesic and antiallodynic effects of apipuncture in a rat neuropathic pain model. DBV (0.25 mg/kg, subcutaneous) was injected into the Zusanli acupoint 2 weeks after chronic constrictive injury (CCI) of the sciatic nerve. Between 5 and 45 minutes after DBV injection, we observed a significant reduction in the thermal hyperalgesia induced by CCI, but apipuncture failed to reduce CCI-induced mechanical allodynia. We subsequently examined whether this antihyperalgesic effect of apipuncture was related to the activation of spinal opioid receptors and/or alpha2-adrenoceptors. Intrathecal pretreatment with naloxone (10 microg/rat), an opioid receptor antagonist, did not reverse the antihyperalgesic effect of apipuncture, whereas pretreatment with idazoxan (40 microg/rat), an alpha2-adrenoceptor antagonist, completely blocked the effect of apipuncture. These results indicate that DBV-induced apipuncture significantly reduces the thermal hyperalgesia generated by CCI and also suggest that this antihyperalgesic effect is dependent on the activation of alpha2-adrenoceptors, but not opioid receptors, in the spinal cord. PERSPECTIVE: The antinociceptive effect of apipuncture was evaluated in a rodent neuropathic pain model. The relieving effect of apipuncture on thermal hyperalgesia was found to be mediated by spinal alpha2-adrenoceptors, but not opioid receptors. These data suggest that apipuncture might be an effective alternative therapy for patients with painful peripheral neuropathy, especially for those who are poorly responsive to opioid analgesics.