Tonic inhibitory control exerted by opioid peptides in the paraventricular nuclei of the hypothalamus on regional hemodynamic activity in rats

Abstract

1. Systemic and regional cardiovascular changes were measured following bilateral microinjection of specific and selective opioid-receptor antagonists into the paraventricular nuclei of the hypothalamus (PVN) of awake, freely moving rats. 2. PVN microinjection of increasing doses of the specific opioid antagonist naloxone - methiodide (1 - 5.0 nmol), or a selective mu-opioid receptor antagonist, beta-funaltrexamine (0.05 - 0.5 nmol), evoked important cardiovascular changes characterized by small and transient increases in heart rate (HR) and mean arterial pressure (MAP), vasoconstriction in renal and superior mesenteric vascular beds and vasodilation in the hindquarter vascular bed. 3. No significant cardiovascular changes were observed following PVN administration of the highly selective delta-opioid-receptor antagonist, ICI 174864 (0.1 - 1 nmol), or the selective kappa-opioid-receptor antagonist, nor-binaltorphine (0.1 - 1 nmol). 4. Most of the cardiovascular responses to naloxone (3 nmol) and beta-funaltrexamine (0.5 nmol) were attenuated or abolished by an i.v. treatment with a specific vasopressin V(1) receptor antagonist. 5. These results suggest that endogenous opioid peptides and mu-type PVN opioid receptors modulate a tonically-active central depressor pathway acting on systemic and regional haemodynamic systems. Part of this influence could involve a tonic inhibition of vasopressin release.

Figure 1

Representative micrograph showing the location of the injection sites (MS, marked with india ink) in the paraventricular nucleus of the hypothalamus (PVN, dashed line represent the limit of the nucleus). GC is the lesion evoked by the guide cannulae. AP=1.4 mm posterior to the bregma. A rat was considered successfully injected when both cannula tips were shown to be slightly above the PVN or within a distance of 0.5 mm of the PVN. 3V, third ventricle; AH, anterior hypothalamic area; AVT, anteroventral thalamic nucleus; F, fornix; GP, globus pallidus; IC, internal capsule; ST, striatum; VLT, ventrolateral thalamic nucleus.

Figure 2

Cardiovascular changes elicited by bilateral microinjection of the vehicle (aCSF, n=12) or increasing doses of naloxone – methiodide (0.1 – 5 nmol, n=12) into the PVN of conscious, unrestrained rats. Values are means±s.e.mean shown by vertical lines. A significant interaction between treatment and time was found for all measured cardiovascular variables. ^*P<0.05 when the cardiovascular responses to naloxone – methiodide at the dose of 1, 3 or 5 nmol are compared with those elicited by the control injection of a CSF.

Figure 3

Changes in regional vascular conductances elicited by bilateral microinjection of the vehicle (aCSF, n=12) or increasing doses of naloxone – methiodide (0.1 – 5 nmol, n=12) into the PVN of conscious, unrestrained rats. These data were derived from the data shown in Figure 2. Values are means±s.e.mean shown by vertical lines. A significant interaction between treatment and time was found for all calculated cardiovascular variables. ^*P<0.05 when the cardiovascular responses to naloxone – methiodide at the dose of 1, 3 or 5 nmol are compared with those elicited by the control injection of aCSF.

Figure 4

Cardiovascular changes elicited by bilateral microinjection of the vehicle (aCSF, n=15) or increasing doses of β-FNA (0.05 – 0.5 nmol, n=15) into the PVN of conscious, unrestrained rats. Values are means±s.e.mean shown by vertical lines. A significant interaction between treatment and time for ΔHR, ΔMAP and ΔRenal and Hindquarter Doppler Shift was found. ^*P<0.05 when the cardiovascular responses to β-FNA at the dose of 0.05 or 0.5 nmol are compared with those elicited by the control injection of aCSF. No significant interaction was observed for ΔMesenteric Doppler Shift, the comparison between β-FNA (at each dose) and the control (aCSF) was done averaging over time.

Figure 5

Changes in regional vascular conductances elicited by bilateral microinjection of the vehicle (aCSF, n=15) or increasing doses of β-FNA (0.05 – 0.5 nmol, n=15) into the PVN of conscious, unrestrained rats. These data were derived from the data shown in Figure 4. Values are means±s.e.mean shown by vertical lines. A significant interaction between treatment and time for ΔRenal and Hindquarter Vascular Conductances was found. ^*P<0.05 when the cardiovascular responses to β-FNA at the dose of 0.05 or 0.5 nmol are compared with those elicited by the control injection of aCSF. No significant interaction was observed for ΔMesenteric Vascular Conductance, the comparison between β-FNA (at each dose) and the control (aCSF) was done averaging over time.

Figure 6

(A) Cardiovascular responses to naloxone – methiodide (3 nmol) or vehicle (aCSF) bilaterally injected into the PVN of conscious rats, in the absence (n=12 for both central injections) or presence (n=12 for naloxone – methiodide; n=11 for aCSF) of intravenous treatment with a vasopressin V₁-receptor antagonist (10 μg kg⁻¹, i.v. bolus, 10 kg⁻¹ h⁻¹, infusion). (B) Cardiovascular responses to β-FNA (0.5 nmol) or vehicle (aCSF) bilaterally injected into the PVN of conscious rats, in the absence (n=15 for both central injections) or presence (n=9 for both central injections) of intravenous treatment with the vasopressin V₁-receptor antagonist. Values are means±s.e.mean shown by vertical lines. (A) A significant interaction between treatment and time was found for all measured cardiovascular variables; (B) A significant interaction between treatment and time was found for ΔHR, ΔMAP and ΔRenal and Hindquarter Doppler Shift. ^*P<0.05 when the cardiovascular responses to naloxone – methiodide or β-FNA in the absence or presence of the vasopressin V₁-receptor antagonist are compared with their respective untreated or intravenously treated control (aCSF) group. †P<0.05, when the cardiovascular responses to naloxone – methiodide or β-FNA in the presence of the vasopressin V₁-receptor antagonist are compared with those elicited in the absence of the vasopressin V₁-receptor antagonist. No significant interaction was observed for ΔMesenteric Doppler Shift, the comparison between β-FNA and the control (aCSF) (in the absence or presence of the vasopressin V1 receptor antagonist) was done averaging over time.

Figure 7

(A) Changes in regional vascular conductances elicited by bilateral microinjection of naloxone – methiodide (3 nmol) or vehicle (aCSF) into the PVN of conscious rats, in the absence (n=12 for both central injections) or presence (n=12 for naloxone – methiodide; n=11 for aCSF) of intravenous treatment with a vasopressin V₁-receptor antagonist (10 μg kg⁻¹, i.v. bolus, 10 kg⁻¹ h⁻¹, infusion). (B) Changes in regional vascular conductances elicited by bilateral microinjection of β-FNA (0.5 nmol) or vehicle (aCSF) into the PVN of conscious rats, in the absence (n=15 for both central injections) or presence (n=9 for both central injections) of intravenous treatment with the vasopressin V₁-receptor antagonist. Values are means±s.e.mean shown by vertical lines. (A) A significant interaction between treatment and time was found for all calculated cardiovascular variables; (B) A significant interaction between treatment and time was found for ΔRenal and ΔHindquarter Vascular Conductances. ^*P<0.05 when the cardiovascular responses to naloxone – methiodide or β-FNA in the absence or presence of the vasopressin V₁-receptor antagonist are compared with their respective untreated or intravenously treated control (aCSF) group. ^†P<0.05, when the cardiovascular responses to naloxone – methiodide or β-FNA in the presence of the vasopressin V₁-receptor antagonist are compared with those elicited in the absence of the vasopressin V₁-receptor antagonist. No significant interaction was observed for ΔMesenteric Vascular Conductance, the comparison between β-FNA and the control (aCSF) (in the absence or presence of the vasopressin V1 receptor antagonist) was done averaging over time.