Novel molecular correlates of endocannabinoid-mediated fear-conditioned analgesia in rats

BackgroundFear-conditioned analgesia (FCA) is the profound suppression of pain during exposure to conditioned aversive stimuli and is mediated at spinal and supraspinal levels. The endocannabinoid system plays a key role in FCA. This study investigated brain and spinal cord expression of genes implicated in pain- and fear-related plasticity (Zif268 and Sgk1), following expression of formalin-evoked nociception, contextual fear or endocannabinoid-mediated FCA. MethodsAdult male Lister-Hooded rats received intra-plantar injection of formalin or saline, with or without administration of the CB1 receptor antagonist AM251 (3mg/kg, i.p.) or vehicle, 30min prior to re-exposure to an arena paired 24h previously with footshock. Real time quantitative polymerase chain reaction was used to measure expression of Zif268 and Sgk1 mRNA in the dorsal horn of the spinal cord (DHSC) and rostral ventromedial medulla (RVM) 30min following arena re-exposure. ResultsIntra-plantar injection of formalin resulted in an increase in Zif268 and Sgk1 mRNA expression in the ipsilateral DHSC of non-fear-conditioned rats, effects not observed in rats expressing FCA. Systemic administration of the CB1 receptor antagonist/inverse agonist AM251 attenuated both FCA and the FCA-associated suppression of Zif268 expression in the ipsilateral DHSC without affecting expression of Sgk1. Conditioned fear was associated with an increase in Zif268 mRNA expression in the RVM of saline-, but not formalin-treated rats. ConclusionsThe present findings suggest that Zif268 in the DHSC is an important molecular correlate of endocannabinoid-mediated FCA, and that fear-related expression of Zif268 in the RVM is influenced by the presence of nociceptive tone.