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

Kooi K. Ang, Robert J. McRitchie, Jane B. Minson, Ida J. Llewellyn-Smith, Paul M. Pilowsky, John P. Chalmers, Leonard F. Arnolda

    Research output: Contribution to journalArticlepeer-review

    26 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)H1552-1558
    Number of pages7
    JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
    Volume276
    Issue number5
    DOIs
    Publication statusPublished - May 1999

    Keywords

    • Enkephalin
    • Naloxone
    • Sympathetic nervous system
    • Sympathoinhibition

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