Bee venom (BV) has traditionally been used in Oriental medicine to relieve pain and to treat inflammatory diseases such as rheumatoid arthritis (RA). While several investigators have evaluated the anti-inflammatory effect of BV treatment, the anti-nociceptive effect of BV treatment on inflammatory pain has not been examined. Previous studies in experimental animals suggest that the therapeutic effect of BV on arthritis is dependent on the site of administration. Because of this potential site specificity, the present study was designed to evaluate the anti-nociceptive effect of BV injections into a specific acupoint (Zusanli) compared to a non-acupoint in an animal model of chronic arthritis. Subcutaneous BV treatment (1 mg/kg per day) was found to dramatically inhibit paw edema caused by Freund's adjuvant injection. Furthermore, BV therapy significantly reduced arthritis-induced nociceptive behaviors (i.e. the nociceptive scores for mechanical hyperalgesia and thermal hyperalgesia). These anti-nociceptive/anti-inflammatory effects of BV were observed from 12 days through 21 days post-BV treatment. In addition, BV treatment significantly suppressed adjuvant-induced Fos expression in the lumbar spinal cord at 3 weeks post-adjuvant injection. Finally, injection of BV into the Zusanli acupoint resulted in a significantly greater analgesic effect on arthritic pain as compared to BV injection in to a more distant non-acupoint. The present study demonstrates that BV injection into the Zusanli acupoint has both anti-inflammatory and anti-nociceptive effects on Freund's adjuvant-induced arthritis in rats. These findings raise the possibility that BV acupuncture may be a promising alternative medicine therapy for the long-term treatment of rheumatoid arthritis.

Immunocytochemical localization of the c-fos primary gene protein, Fos, was used to identify spinal cord and brain-stem sites activated by either 4-Hz or 100-Hz electroacupuncture (EA) applied to the Zusanli acupuncture points of both hind limbs in lightly anesthetized Sprague-Dawley rats. The number and distribution of Fos-immunoreactive neurons in the brain stem and spinal cord of 4-Hz and 100-Hz EA-treated rats were compared with these in anesthesia and room control rats. Compared to non-stimulated control rats or rats in which EA was applied to a non-acupuncture point, both 4-Hz and 100-Hz EA-treated groups exhibited a significantly greater number of Fos-labeled neurons in the dorsal horn of the L2 spinal cord segment, lateral parabrachial nucleus, substantia nigra, nucleus raphe pallidus, dorsal raphe, locus coeruleus, posterior pretectal nucleus, and the lateroventral periaqueductal gray. In the 4-Hz-treated group, significant increases in Fos labeling were also observed in the cuneiform nucleus, dorsal and laterodorsal subdivisions of the periaqueductal gray, habenular nucleus, arcuate hypothalamic nucleus, and the lateroventral and lateral hypothalamic nuclei as compared to non-stimulated controls. The only brain-stem nucleus that exhibited significantly increased Fos-immunoreactive neurons in 100-Hz but not 4-Hz EA was the rostolateroventral nucleus of the medulla. These results indicate that many brain-stem regions are activated by both 4-Hz and 100-Hz EA but additional brain-stem regions are selectively activated by 4-Hz EA which may relate to the opiate sensitivity of 4-Hz EA. In sum, these data identify several distinct brain-stem nuclei that may play a role in acupuncture-mediated analgesia.

THE ς¹receptor (Sig-1R) plays an important role in a variety of cellular functions and biologic processes.1,2 It is well recognized that Sig-1Rs are present throughout the central nervous system and are highly expressed in the olfactory bulb, certain cortical areas, the amygdala, the hypothalamus, the periaqueductal gray, and the dorsal horn of the spinal cord.3 Recently, it has been shown that the Sig-1R has a pronociceptive effect in formalin-induced pain using Sig-1R knockout mice.4 Further support for a pronociceptive role for this receptor comes from a study demonstrating that systemic administration of the putative Sig-1R antagonist haloperidol markedly reduces nociceptive behaviors in both phases of the formalin test.5 In addition, a recent study from our laboratories reported that intrathecal pretreatment with the Sig-1R antagonist BD-1047 or BMY-14802 reduces nociceptive behaviors and spinal Fos expression associated with the formalin test.6 Although a role for spinal cord Sig-1Rs has been established for acute pain using the formalin test, it is currently not known whether Sig-1Rs contribute to the induction or maintenance of chronic pain conditions.

Background and purpose: Previously we demonstrated that the spinal sigma‐1 receptor (Sig‐1 R) plays an important role in pain transmission, although the exact mechanism is still unclear. It has been suggested that Sig‐1 R agonists increase glutamate‐induced calcium influx through N‐methyl‐D‐aspartate (NMDA) receptors. Despite data suggesting a link between Sig‐1 Rs and NMDA receptors, there are no studies addressing whether Sig‐1 R activation directly affects NMDA receptor sensitivity.Experimental approach: We studied the effect of intrathecal (i.t.) administration of Sig‐1 R agonists on protein kinase C (PKC) and protein kinase A (PKA) dependent phosphorylation of the NMDA receptor subunit NR1 (pNR1) as a marker of NMDA receptor sensitization. In addition, we examined whether this Sig‐1 R mediated phosphorylation of NR1 plays an important role in sensory function using a model of NMDA‐induced pain.Key results: Both Western blot assays and image analysis of pNR1 immunohistochemical staining in the spinal cord indicated that i.t. injection of the Sig‐1 R agonists, PRE‐084 or carbetapentane dose dependently enhanced pNR1 expression in the murine dorsal horn. This increased pNR1 expression was significantly reduced by pretreatment with the specific Sig‐1 R antagonist, BD‐1047. In another set of experiments Sig‐1 R agonists further potentiated NMDA‐induced pain behaviour and pNR1 immunoreactivity and this was also reversed with BD‐1047.Conclusions and implications: The results of this study suggest that the activation of spinal Sig‐1 R enhances NMDA‐induced pain via PKC‐ and PKA‐dependent phosphorylation of the NMDA receptor NR 1 subunit.British Journal of Pharmacology (2008) 154, 1125–1134; doi:10.1038/bjp.2008.159; published online 19 May 2008