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  • Both anxiogenic and antinociceptive effects produced by

    2019-07-02

    Both anxiogenic and antinociceptive effects produced by CRF seem to be selective for the CRF1 receptor, since intra-dPAG microinjection of ASV 30, a CRF2 receptor antagonist, altered neither the anxiety nor the antinociception response. Intra-dPAG ASV 30 was also unable to prevent the anxiogenic (observed in both conventional and ethological anxiety-related measures) and antinociceptive effects produced by local infusion of CRF. Thus, despite their presence in all columns of the PAG (Steckler and Holsboer, 1999), CRF2 receptors do not play a role in anxiety, assessed in the EPM, or in nociception assessed in the formalin test in mice. Regarding the effects of CRF on anxiety, Sahuque et al. (2006) have demonstrated that this neuropeptide also enhances anxiety when injected into the bed nucleus of the stria terminalis (BNST), a thapsigargin structure that has also been related to defensive behavior (Casada and Dafny, 1991, Chen et al., 2009, Walker et al., 2003). Those authors also demonstrated that intra-BNST injections of a CRF1 (but not CRF2) receptor antagonist prevented the anxiogenic effect produced by CRF. Importantly, Sahuque et al. (2006) demonstrated that intra-BNST ASV 30, at the same dose employed in the present study, was able to prevent place aversion induced by local CRF injection, but did not attenuate the anxiogenic effect produced by this neuropeptide in rats exposed to the EPM. In view of these findings, it seems that the emotional state elicited by EPM exposure does not recruit CRF2 receptors located within the BNST (Sahuque et al., 2006) and dPAG (present results) in rats and mice, respectively. It has been thapsigargin demonstrated that CRF has a higher affinity for CRF1 receptors than for CRF2 receptors (Vaughan et al., 1995). This differential affinity might be the main reason for the presently observed lack of effect of ASV 30 on the anxiogenic and antinociceptive effects produced by CRF. However, it has been reported that the anxiogenic-like effects produced with i.c.v. injections of CRF (200pmol) in mice exposed to the startle paradigm were attenuated with i.c.v. injection of ASV 30 (Risbrough et al., 2003), at a similar dose to that used in the present study. Therefore, it is likely that the dose of 150pmol of CRF, which was directly injected into the dPAG, has been sufficiently high to activate CRF2 receptors in the present study. Moreover, while i.c.v. injection of a selective CRF1 receptor agonist, stressin-1A, produces anxiogenic-like effects in rats exposed to the shock probe test, no effects were observed with urocortine III, a selective CRF2 receptor agonist (Zhao et al., 2007). These inconsistent results indicate a need for further studies with different animal models of anxiety to better understand the role of CRF2 receptors in the neurobiology of emotional states. In this context, the present results indicate that the PAG CRF1 (but not CRF2) receptor is an important target on which CRF exerts its anxiogenic-like actions in mice exposed to the EPM. Finally, it has been emphasized that the PAG receives CRF-containing neuron projections from other anxiety-related brain structures such as amygdala, hypothalamus and BNST (Gray and Magnuson, 1992). Furthermore, studies in vitro have shown an excitatory effect on PAG neurons following CRF administration (Bowers et al., 2003). Thus, the CRF anxiogenic and antinociceptive actions observed in the present study might be associated with a neuron-firing response as a consequence of membrane depolarization provoked by this neuropeptide within the PAG. Although both CRF1 and CRF2 receptors have been found in the PAG (Merchenthaler, 1984, Swanson et al., 1983), present results suggest that the anxiogenic and the antinociceptive effects of CRF introduced into the dPAG are related to CRF1 but not CRF2 receptor activation. However, given the contrasting effects observed with manipulation of CRF2 receptors in emotional tests (Bale et al., 2000, Kishimoto et al., 2000, Radulovic et al., 1999, Risbrough et al., 2003, Takahashi et al., 2001, Zhao et al., 2007), it is important to point out that further studies are needed to determine the role played by this CRF receptor subtype in the nociception response as well as in anxiety-related behavior.