Comparison between C57BL/6N and C57BL/6J for their systolic blood pressure and heart rate responses to various salt challenges measured by NIBP.

<p>Measurements were made during the dark periods of a modified light/dark cycle. NS = normal salt diet (n = 20 and n = 20, for C57BL/6N and C57BL/6J respectively), LS = low salt diet (n = 20 and n = 20, for C57BL/6N and C57BL/6J respectively), HS = high Na⁺/normal K⁺ diet (n = 9 and n = 10, for C57BL/6N and C57BL/6J respectively) and HS/LK = high Na⁺/low K⁺ diet (n = 9 and n = 10, for C57BL/6N and C57BL/6J respectively). One-way ANOVA per light phase followed by Tukey Kramer’s post-hoc test; #: p<0.05 HS/LK compared to HS.</p

Plasma ion, aldosterone and renin activity measurements in C57BL/6N and C57BL/6J male mice.

<p>Plasma ion, aldosterone and renin activity measurements in C57BL/6N and C57BL/6J male mice.</p

Comparison between C57BL/6N and C57BL/6J for their mean blood pressure and heart rate responses to various salt challenges.

<p>Mice were monitored with telemetry during the dark (A, B) and light (C) periods of a modified light/dark cycle. NS = normal salt diet (n = 17 and n = 17, for C57BL/6N and C57BL/6J respectively), LS = low salt diet (n = 15 and n = 17, for C57BL/6N and C57BL/6J respectively), HS = high Na⁺/normal K⁺ diet (n = 8 and n = 8, for C57BL/6N and C57BL/6J respectively) and HS/LK = high Na⁺/low K⁺ diet (n = 6 and n = 9, for C57BL/6N and C57BL/6J respectively). One-way ANOVA per light phase followed by Tukey’s post-hoc test; *: p<0.05 compared to NS diet; #: p<0.05 HS/LK compared to HS.</p

Effect of high salt diets on the circadian blood pressure variations in C57BL/6N and C57BL/6J mice under a reverse light/dark cycle.

<p>2.5 days continuous telemetric recordings of systolic blood pressure after 2 weeks of NS, HS or HS/LK diet challenge. A) n = 8 per group B) n = 6 per group C) n = 8 per group D) n = 9 per group. Two-way ANOVA followed by Sidak’s post-hoc test *: p<0.05 for interaction.</p

Sodium and potassium levels in urine and plasma in C57BL/6N.

<p>Sodium and potassium levels in urine and plasma in C57BL/6N.</p

Effects of high-salt/normal potassium and high-salt/low potassium on mean blood pressure and heart rate in C57BL/6N mice.

<p>Mice were monitored with telemetry in the dark (A, B, C) and light (C) periods of a modified light/dark cycle. NS = normal salt diet (n = 17), LS = low salt diet (n = 15), HS = high Na⁺/normal K⁺ diet (n = 8) and HS/LK = high Na⁺/low K⁺ diet (n = 6). One-way ANOVA per light phase followed by Tukey’s post-hoc test; *: p<0.05 compared to NS diet; #: p<0.05 HS/LK compared to HS.</p

Effects of various salt challenges on mean blood pressure and heart rate in C57BL/6N male mice.

<p>Mice were monitored with telemetry and placed in a standard (A, C) or modified light/dark cycle (B, D). NS = normal salt diet (n = 12 and n = 17, for the standard and modified light cycle respectively), LS = low salt diet (n = 11 and n = 15, for the standard and modified light cycle respectively), HS = high Na⁺/normal K⁺ diet (n = 5 and n = 6, for the standard and modified light cycle respectively). One-way ANOVA per light phase followed by Tukey’s post-hoc test; *: p<0.05 compared to NS diet.</p

RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents

Although opiates represent the most effective analgesics, their use in chronic treatments is associated with numerous side effects including the development of pain hypersensitivity and analgesic tolerance. We recently identified a novel orally active neuropeptide FF (NPFF) receptor antagonist, RF313, which efficiently prevents the development of fentanyl-induced hyperalgesia in rats. In this study, we investigated the properties of this compound into more details. We show that RF313 exhibited a pronounced selectivity for NPFF receptors, antagonist activity at NPFF1 receptor (NPFF1R) subtype both in vitro and in vivo and no major side effects when administered in mice up to 30 mg/kg. When co-administered with opiates in rats and mice, it improved their analgesic efficacy and prevented the development of long lasting opioid-induced hyperalgesia. Moreover, and in marked contrast with the dipeptidic NPFF receptor antagonist RF9, RF313 displayed negligible affinity and no agonist activity (up to 100 μM) toward the kisspeptin receptor. Finally, in male hamster, RF313 had no effect when administered alone but fully blocked the increase in LH induced by RFRP-3, while RF9 per se induced a significant increase in LH levels which is consistent with its ability to activate kisspeptin receptors. Altogether, our data indicate that RF313 represents an interesting compound for the development of therapeutic tools aiming at improving analgesic action of opiates and reducing adverse side effects associated with their chronic administration. Moreover, its lack of agonist activity at the kisspeptin receptor indicates that RF313 might be considered a better pharmacological tool, when compared to RF9, to examine the regulatory roles of RF-amide-related peptides and NPFF1R in reproduction