Prevention of isolation‐induced hypertension by intrahippocampal administration of a nonpeptide kappa‐opioid receptor agonist

Abstract

Previous research in this laboratory showed that hypertension in the spontaneous hypertensive rat (SHR) appears to correlate to insufficient production of hippocampal dynorphins, and that blood pressure could be reduced by intrahippocampal administration of dynorphins and nonpeptide kappa agonists. The purpose of the present study was to investigate whether kappa agonists could prevent the development of hypertension in a different hypertensive model, i.e., the isolated male rat model of hypertension (IHR). Isolation of young male rats for 5-7 days in standard rat cages caused an increase in systolic blood pressure from a mean of 132 to 184 mmHg. The blood pressures of rats grouped 3 per cage remained stable. Rats received the nonpeptide kappa agonist U62, 066E, (Spiradoline, Upjohn), 10 nmoles/0.2 microl or drug vehicle bilaterally into the the hippocampus for 3 days prior to and during isolation or grouping. Animals treated with U62, 066E did not develop hypertension as compared to isolated animals treated with vehicle. The isolation procedure used in these studies appears to induce anxietal stress, as indicated by reduced time spent by the rats in the open arms of the elevated-plus maze. This time is increased by U62, 066E, suggesting that the drug possesses anxiolytic properties and may reduce hypertension in part, by blocking an anxiety/stress component. These data strengthen our previous findings that opioids in the hippocampus may be important in restraining increased blood pressure provoked by environmental stimuli such as isolation.

Concordance and incongruence in preclinical anxiety models: systematic review and meta-analyses

“…Meta-analysis of fifteen articles (Rodgers and Cole, 1993;Haller et al, 2000;Blednov et al, 2001;Cheeta et al, 2001;Lapiz et al, 2001;Wright and Ingenito, 2001;Majercsik et al, 2003;Moragrega et al, 2003;Abramov et al, 2004;Wei et al, 2007;Koike et al, 2009;Santos et al, 2010;Cuenya et al, 2012;Lukkes et al, 2009;Hermes et al, 2011) on social isolation revealed it had a small anxiogenic effect (g = 0.37 [95CI 0.15, 0.58], p = 7.8 x 10 -4 ; Figure 6C). However, Egger's regression revealed funnel plot asymmetry, while trim-and-fill adjustment reduced the anxiogenic effect to only 0.15 g [95CI -0.10, 0.40], a small and statistically non-significant effect on ARDEB ( Figure 2).…”

“…2008; Quintino-dos-Santos et al, 2014; F. M. C. V. Reis et al, 2012;Rodgers and Cole, 1993;Ryu et al, 2009;Santos et al, 2010;Serra et al, 2000;Thorsell et al, 2006;Voikar et al, 2005;Wei et al, 2007;Workman et al, 2011;Wright and Ingenito, 2001;Yildirim et al, 2012;Yorgason et al, 2013;Y. Zhang et al, 2012).…”

“…Heterogeneity : I^2=13.1%, Tau^2=0, p=0.3278 Gammie, 2006 -Fitzwater et al, 2009;Estelles et al, 2007;Fone et al, 1996;Haller and Halász, 1999;Haller et al, 2000;Hermes et al, 2011;Hirani et al, 2005;Imanaka et al, 2008;Knuth and Etgen, 2007;Koike et al, 2009;Kokare et al, 2010;Lapiz et al, 2001;Leussis and Andersen, 2008;Linge et al, 2013;Xiao Liu et al, 2013;Lukkes et al, 2009;Majercsik et al, 2003;McCool and Chappell, 2009;Moragrega et al, 2003;Pisu et al, 2013;Pritchard et al, 2008;Quintino-dos-Santos et al, 2014; F. M. C. V. Reis et al, 2012;Rodgers and Cole, 1993;Ryu et al, 2009;Santos et al, 2010;Serra et al, 2000;Thorsell et al, 2006;Voikar et al, 2005;Wei et al, 2007;Workman et al, 2011;Wright and Ingenito, 2001;Yildirim et al, 2012;Yorgason et al, 2013;Y. Zhang et al, 2012).…”

“…Zhang et al 2012;Yildirim, Erol, and Ulupinar 2012;Djordjevic et al 2012;Workman et al 2011;Hermes et al 2011;Conrad et al 2011;Bledsoe et al 2011;Pisu et al 2011;Kokare et al 2010;Santos, de Andrade, and Graeff 2010;Ryu et al 2009;H. Koike et al 2009;Doremus-Fitzwater, Varlinskaya, and Spear 2009;McCool and Chappell 2009;Brenes, Padilla, and Fornaguera 2009;Lukkes et al 2009;Imanaka et al 2008;Leussis and Andersen 2008;Pritchard et al 2008;Wei et al 2007;Knuth and Etgen 2007;Estelles et al 2007;Imanaka et al 2006;Blakley and Pohorecky 2006;Thorsell et al 2006;Hirani et al 2005;Voikar et al 2005;Abramov et al 2004;Moragrega et al 2003;Majercsik et al 2003;Blednov et al 2001;Lapiz et al 2001;Cheeta, Irvine, and File 2001;Wright and Ingenito 2001;Haller, Halász, and Makara 2000;Serra et al 2000;Haller and Halász 1999;Da Silva et al 1996;Fone et al 1996;Rodgers and Cole 1993;…”

Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment

“…While KOR antagonists have been at the forefront of treatment options for psychiatric illnesses, they are also implicated in a medley of other physiological disorders, including salt consumption (Nascimento et al 2012), epilepsy and hypertension (though hypertension is not discussed here, see(Wright & Ingenito 2001, Wright & Ingenito 2003, Wright et al 2000) for further reading). This brings together the importance of the “whole body” perspective when considering KOR drugs as therapeutic treatment for brain-related diseases.…”