Activation of spinal opioid receptors contributes to hypotension after hemorrhage in conscious rats

Abstract

Opioid receptors are activated during severe hemorrhage, resulting in sympathoinhibition and a profound fall in blood pressure. This study examined the location and subtypes of opioid receptors that might contribute to hypotension after hemorrhage. Intrathecal naloxone methiodide (100 nmol) abolished the fall in blood pressure after hemorrhage (1.5% of body wt; mean arterial pressure 122 ± 8 mmHg after naloxone methiodide vs. 46 ± 5 mmHg in controls, P < 0.001). Intracisternal naloxone methiodide was less effective than intrathecal naloxone methiodide, whereas intravenous naloxone methiodide, which does not cross the blood-brain barrier, did not alter the fall in blood pressure after hemorrhage. These results demonstrate that spinal opioid receptors contribute to hypotension after hemorrhage but do not exclude supraspinal effects. In separate experiments, the subtype-specific opioid antagonists ICI-174864 (δ-antagonist), norbinaltorphimine (nor-BNI; κ-antagonist), and H-d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2(CTOP; μ-antagonist) were each administered intrathecally to determine the minimum dose that would attenuate hypotension during severe hemorrhage. These antagonists were effective at similar doses (3 nmol for CTOP, 6 nmol for ICI-174864, and 10 nmol for nor-BNI), although the binding affinities of these three different agents for their target receptors varied >1600-fold. Comparisons of the minimum effective doses of these antagonists in relation to their binding affinities provides strong evidence for the participation of δ-receptors in mediating hypotension after hemorrhage. In contrast, the dose at which nor-BNI was effective suggests an effect at δ-receptors but not κ-receptors. The efficacy of CTOP, albeit at a high dose, also suggests an effect at μ-receptors.

Preproenkephalin mRNA is expressed by C1 and non‐C1 barosensitive bulbospinal neurons in the rostral ventrolateral medulla of the rat

“…Major blood loss is associated with an initial increase in sympathetic nerve activity to maintain AP, but is followed by a seemingly paradoxical decrease in sympathetic nerve activity and precipitous fall in AP (Morita et al, 1988;Thoren et al, 1988). The ability of the opiate receptor antagonist naloxone administered intrathecally to attenuate the hemorrhage-induced hypotension is consistent with the release of enkephalin at a spinal site during severe hemorrhage (Ang et al, 1999). ACKNOWLEDGMENT P.G.G.…”

Dysphagia and disrupted cranial nerve development in a mouse model of DiGeorge/22q11 Deletion Syndrome

“…Dysphagia – disrupted feeding, swallowing and nutrition – is a serious complication of several developmental disorders, including 22q11 deletion syndrome (22q11DS) (Christensen, 1989; Ang et al, 1999; Eicher et al, 2000; Schwarz et al, 2001; Rommel et al, 2008). Perinatal dysphagia is especially challenging to manage (Schwarz et al, 2001; Kelly, 2006; Lefton-Greif, 2008), and frequently results in aspiration-based infection and other complications (Hopkin et al, 2000; Trinick et al, 2012).…”

Mechanosensitive cardiac C-fiber response to changes in left ventricular filling, coronary perfusion pressure, hemorrhage, and volume expansion in rats

“…The efferent limb of this reflex response has been extensively investigated. Central opioid and serotonin pathways in different brain stem regions seem to be involved in the second-phase sympathoinhibitory response (7,21,32,35,51) as well as peripheral and spinal cord opioid receptors (2,5), because appropriate administration of receptor blockers blunted the response. Furthermore, RSNA response seems to be modulated by high vasopressin levels in the setting of hemorrhage, whereas vasopressin receptors exert an inhibitory action on RSNA and contribute to blood pressure recovery via V1 receptors but exerts an opposite stimulatory action on RSNA via V2 receptors (19).…”