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

Although previous reports have suggested that the sigma 1 (σ₁) receptor may be involved in pain sensation, its specific site of action has not been elucidated. The aim of present study was to determine the role of the spinalσ₁receptor in formalin‐induced pain behavior, spinal cord Fos expression and phosphorylation ofN‐methyl‐D‐aspartate receptor subunit 1 (pNR1). Intrathecal (i.t.) pretreatment with the selectiveσ₁receptor antagonist, BD‐1047 (N‐[2‐(3,4‐dichlorophenyl)ethyl]‐N‐methyl‐2‐(dimethylamino)ethylamine dihydrobromide) (10–100 nmol) dose dependently reduced formalin‐induced pain behaviors in second phase, but not first phase, of the formalin test. I.t. injection of BD‐1047 also reduced formalin‐evoked Fos expression and pNR1 at the protein kinase C‐dependent site, serine‐896 (Ser896) and the protein kinase A‐dependent site, serine‐897 (Ser897) in spinal dorsal horn. i.t. BMY‐14802 ((α‐(4‐fluorophenyl)‐4‐(5‐fluoro‐2‐pyrimidinyl)‐1‐piperazinebutanol hydrochloride) (10–100 nmol,σ₁receptor antagonist and 5‐HT_1Areceptor agonist) dose dependently reduced formalin‐induced pain behaviors in both phases. However, the 5‐HT_1Areceptor might not be involved in the antinociceptive effect of BMY‐14802 on the second phase, since i.t. pretreatment with the 5‐HT_1Areceptor antagonist propranolol ((S)‐1‐isopropylamino‐3‐(1‐naphthyloxy)‐2‐propanol hydrochloride) (injected 10 min prior to i.t. BMY‐14802) partially blocked the effect of BMY‐14802 on the first phase of the formalin test but did not affect the inhibitory effect of BMY‐14802 on the second phase. In addition, i.t. BMY‐14802 significantly reduced formalin‐evoked Fos expression and pNR1 (Ser896 and Ser897) expression in spinal dorsal horn. The results of this study suggest that selective blockage of spinalσ₁receptors can reduce pain behaviors, spinal cord Fos expression and pNR1 (Ser896 and Ser897) expression associated with the second phase of the formalin test. British Journal of Pharmacology(2006)148, 490–498. doi:10.1038/sj.bjp.0706764

In two previous reports, we have demonstrated that injection of bee venom (BV) into an acupoint produces a significant antinociceptive and anti-inflammatory effect in both a mouse model of visceral nociception and a rat model of chronic arthritis. The present study was designed to evaluate the potential antinociceptive effect of BV pretreatment on formalin-induced pain behavior and it associated spinal cord Fos expression in rats. Adult Sprague-Dawley rats were injected with BV directly into the Zusanli (ST36) acupoint or into an arbitrary non-acupoint located on the back. BV pretreatment into the Zusanli acupoint significantly decreased paw-licking time in the late phase of the formalin test. In contrast, BV injected into a non-acupoint in the back region did not suppress the paw-licking time. In addition, BV pretreatment into the Zusanli acupoint markedly inhibited spinal cord Fos expression induced by formalin injection. These findings indicate that BV pretreatment into the Zusanli acupoint has an antinociceptive effect on formalin-induced pain behavior.

Kwon YB, et al. J Vet Sci. 2006 Jun;7(2):105-109. https://doi.org/10.4142/jvs.2006.7.2.105