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

Opioid receptors are activated during severe hemorrhage, resulting in sympa thoinhibition and a profound fall in blood pressure. This study examined th e location and subtypes of opioid receptors that might contribute to hypote nsion after hemorrhage. Intrathecal naloxone methiodide (100 nmol) abolishe d the fall in blood pressure after hemorrhage (1.5% of body wt; mean arteri al pressure 122 +/- 8 mmHg after naloxone methiodide vs. 46 +/- 5 mmHg in c ontrols, P < 0.001). Intracisternal naloxone methiodide was less effective than intrathecal naloxone methiodide, whereas intravenous naloxone methiodi de, which does not cross the blood-brain barrier, did not alter the fall in blood pressure after hemorrhage. These results demonstrate that spinal opi oid receptors contribute to hypotension after hemorrhage but do not exclude supraspinal effects. In separate experiments, the subtype-specific opioid antagonists ICI-174864 (delta-antagonist), norbinaltorphimine (nor-BNI; kap pa-antagonist), and H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; mu-ant agonist) were each administered intrathecally to determine the minimum dose that would attenuate hypotension during severe hemorrhage. These antagonis ts 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 d ifferent agents for their target receptors varied >1600-fold. Comparisons o f the minimum effective doses of these antagonists in relation to their bin ding affinities provides strong evidence for the participation of delta-rec eptors in mediating hypotension after hemorrhage. In contrast, the dose at which nor-BNI was effective suggests an effect at delta-receptors but not k appa-receptors. The efficacy of CTOP, albeit at a high dose, also suggests an effect at mu-receptors.