Intrathecal treatment with σ1 receptor antagonists reduces formalin-induced phosphorylation of NMDA receptor subunit 1 and the second phase of formalin test in mice

Abstract

1 Although previous reports have suggested that the sigma 1 (s1) 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 spinal s1 receptor in formalin-induced pain behavior, spinal cord Fos expression and phosphorylation of N-methyl-D-aspartate receptor subunit 1 (pNR1). 2 Intrathecal (i.t.) pretreatment with the selective s1 receptor 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. 3 i.t. BMY-14802 ((a-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride) (10–100 nmol, s1 receptor antagonist and 5-HT1A receptor agonist) dose dependently reduced formalin-induced pain behaviors in both phases. However, the 5-HT1A receptor might not be involved in the antinociceptive effect of BMY-14802 on the second phase, since i.t. pretreatment with the 5-HT1A receptor 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. 4 The results of this study suggest that selective blockage of spinal s1 receptors can reduce pain behaviors, spinal cord Fos expression and pNR1 (Ser896 and Ser897) expression associated with the second phase of the formalin test.