26 research outputs found

    The effects of rapid infusions of saline and mannitol on cerebral blood volume and intracranial pressure in dogs

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    The role of osmotic brain dehydration in the early reduction of intracranial pressure (ICP) following mannitol administration has recently been questioned and a decrease in cerebral blood volume (CBV) proposed as the mechanism of action. To evaluate this hypothesis, relative CBV changes before and after mannitol infusion were determined by collimated gamma counting across the biparietal diameter of the exposed skull in six dogs. Red blood cells were labelled with chromium-51. Cerebral blood volume (CBV), total blood volume (TBV), ICP, mean arterial pressure (MAP), central venous pressure (CVP), haematocrit and osmolality were serially measured after infusions of 10 ml X kg-1 of normal saline (control study) and of 20 per cent mannitol (mannitol study). The solutions were administered over a two-minute period; a 30-minute equilibration period intervened between the saline and mannitol infusions. We demonstrated that the mannitol infusion was associated with significant increases in relative CBV (25 per cent), ICP (7 mmHg), CVP (11 cm H2O), and TBV (50 per cent). MAP declined significantly (14 per cent) after mannitol infusion. The administration of saline, although associated with an increase in TBV (18 per cent), was not associated with any significant change in CBV, ICP, MAP or CVP. The increase in relative CBV persisted for 15 minutes after mannitol infusion, while the ICP returned to control within five minutes and continued to decrease. This study supports the fact that after rapid mannitol infusion, ICP begins to decrease only once the dehydrating effect has counteracted the increase in brain bulk caused by the increase in cerebral blood volume

    Effects of rapid mannitol infusion on cerebral blood volume. A positron emission tomographic study in dogs and man

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    Positron emission tomography was used to study the effect of a rapid infusion of mannitol on cerebral blood volume (CBV) in five dogs and in three human subjects. The ability of mannitol to reduce intracranial pressure (ICP) has always been attributed to its osmotic dehydrating effect. The effects of mannitol infusion include increased osmolality, total blood volume, central venous pressure (CVP), and cerebral blood flow, and decreased hematocrit, hemoglobin concentration, serum sodium level, and viscosity. Mannitol's ability to dilate the cerebral vasculature, either directly or indirectly, and thus to transiently increase ICP, is a subject of controversy. By in vivo labeling of red cells with carbon-11, the authors were able to demonstrate an early increase in CBV in dogs of 20%, 27%, and 23% (mean increase, p less than 0.05) at 1, 2, and 3 minutes, respectively, after an infusion of 20% mannitol (2 gm/kg over a 3-minute period). The animals' muscle blood volume increased by 27% (mean increase, p less than 0.05) 2 minutes after infusion. In the human subjects, lower doses and a longer duration of infusion (1 gm/kg over 4 minutes) resulted in an increase in CBV of 8%, 14% (p less than 0.05), and 10% at 1, 2, and 3 minutes, respectively, after infusion. In dogs, ICP increased by 4 mm Hg (mean increase, p less than 0.05) 1 minute after the infusion, before decreasing sharply. The ICP was not measured in the human subjects. Hematocrit, hemoglobin, sodium, potassium, osmolality, heart rate, mean arterial pressure (MAP), and CVP were measured serially. Results of these measurements, as well as the significant decrease in MAP that occurred after mannitol infusion, are discussed. This study demonstrated that rapid mannitol infusion increases CBV and ICP. The increase in muscle blood volume, in the presence of a decreased MAP and an adequate CVP, suggests that mannitol may have caused vasodilation in these experiments

    Intrathecal Delivery of a Mutant μ-Opioid Receptor Activated by Naloxone as a Possible Antinociceptive Paradigm

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    Direct injection of double-stranded adeno-associated virus type 2 (dsAAV2) with a μ-opioid receptor (MOR) mutant [S4.45(196)A], and a reporter protein (enhanced green fluorescent protein) into the spinal cord (S2/S3) dorsal horn region of ICR mice resulted in antinociceptive responses to systemic injection of opioid antagonist naloxone without altering the acute agonist morphine responses and no measurable tolerance or dependence development during subchronic naloxone treatment. To develop further such mutant MORs into a therapeutic agent in pain management, a less invasive method for virus delivery is needed. Thus, in current studies, the dsAAV2 was locally injected into the subarachnoid space of the spinal cord by intrathecal administration. Instead of using the MORS196A mutant, we constructed the dsAAV2 vector with the MORS196ACSTA mutant, a receptor mutant in which naloxone has been shown to exhibit full agonistic properties in vitro. After 2 weeks of virus injection, naloxone (10 mg/kg s.c.) elicited antinociceptive effect (determined by tail-flick test) without tolerance (10 mg/kg s.c., b.i.d. for 6 days) and significant withdrawal symptoms. On the other hand, subchronic treatment with morphine (10 mg/kg s.c., b.i.d.) for 6 days induced significant tolerance (4.8-fold) and withdrawal symptoms. Furthermore, we found that morphine, but not naloxone, induced the rewarding effects (determined by conditioned place preference test). These data suggest that local expression of MORS196ACSTA in spinal cord and systemic administration of naloxone has the potential to be developed into a new strategy in the management of pain without addiction liability
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