Hypertensive Effect of Downregulation of the Opioid System in Mouse Model of Different Activity of the Endogenous Opioid System

Abstract

The opioid system is well-known for its role in modulating nociception and addiction development. However, there are premises that the endogenous opioid system may also affect blood pressure. The main goal of the present study was to determine the impact of different endogenous opioid system activity and its pharmacological blockade on blood pressure. Moreover, we examined the vascular function in hyper- and hypoactive states of the opioid system and its pharmacological modification. In our study, we used two mouse lines which are divergently bred for high (HA) and low (LA) swim stress-induced analgesia. The obtained results indicated that individuals with low endogenous opioid system activity have higher basal blood pressure compared to those with a hyperactive opioid system. Additionally, naloxone administration only resulted in the elevation of blood pressure in HA mice. We also showed that the hypoactive opioid system contributes to impaired vascular relaxation independent of endothelium, which corresponded with decreased guanylyl cyclase levels in the aorta. Together, these data suggest that higher basal blood pressure in LA mice is a result of disturbed mechanisms in vascular relaxation in smooth muscle cells. We believe that a novel mechanism which involves endogenous opioid system activity in the regulation of blood pressure will be a promising target for further studies in hypertension development.

Prenatal Morphine Exposure Increases Cardiovascular Disease Risk and Programs Neurogenic Hypertension in the Adult Offspring

“…72 Furthermore, naloxone administration attenuated the development of hypertension in the spontaneously hypertensive rat model known to show sympathetic and RAS activation. 20,28,29 In the current study, the Ang II-induced ex vivo constriction was increased in IUME rats while the expression of AT1R and ACE were downregulated in the aorta, heart, and kidney (data not shown). This finding suggests the increased Ang IIinduced constriction is most likely facilitated by the ORs, potentially increasing the affinity to AT1R and amplifying the signaling cascade, as we showed that blocking ORs with naloxone can revert this effectherefore, IUME could induce chronic activation of the AT1R potentially enhanced by the heterodimerization with µ-OR, resulting in reduced AT1R expression.…”

“…Preclinical reports have shown opiates as important modulators of cardiovascular function in both normotensive and hypertensive states, and studies have reported that EOPs are elevated in models of hypertension of various causes, including genetic and renovascular hypertension. 29,74 The levels of EOPs fluctuate during the lifespan. Physiologically, β-endorphin plasma levels increase during pregnancy from week 6 (20 fmol/mL) to delivery (>120 fmol/mL).…”

“…[27][28][29] Although numerous preclinical studies of prenatal opioid exposure have been used to investigate long-term consequences in behavior outcomes, analgesia, reward, learning, and memory processing, only a handful of studies have assessed the detrimental effects of opioid use on cardiovascular function. 12,[29][30][31] Moreover, the study of potential sex differences secondary to prenatal opioid exposure has been lacking altogether. 31 Consequently, there is a remarkable gap in the knowledge addressing the link between opioid exposure during developmental life and long-term cardiovascular risk.…”

“…[23][24][25][26] Moreover, the peripheral expression of ORs subtypes in the vasculature have been shown to play a role in endothelial function by impairing or improving vascular relaxation upon the activation of mu-OR or K-OR, respectively. [27][28][29] Although numerous preclinical studies of prenatal opioid exposure have been used to investigate long-term consequences in behavior outcomes, analgesia, reward, learning, and memory processing, only a handful of studies have assessed the detrimental effects of opioid use on cardiovascular function. 12,[29][30][31] Moreover, the study of potential sex differences secondary to prenatal opioid exposure has been lacking altogether.…”

The Role of Opioid Receptor Antagonists in Regulation of Blood Pressure and T-Cell Activation in Mice Selected for High Analgesia Induced by Swim Stress

“…In our previous study, we found that HA mice had an increased BP when exposed to NAL for one week. Interestingly, mice with low swim stress-induced analgesia (LA) had a higher basal BP level than HA mice, but NAL treatment had no effect on BP [ 13 ]. Therefore, in this study, we aimed to further investigate this effect using selective opioid receptor antagonists to evaluate which opioid receptors (μ, δ, or κ) influence the BP level.…”