Alexander Nemirovsky

The antinociceptive effect of the combination of spinal morphine with systemic morphine or buprenorphine.

We sought to analyze the mode of interaction of spinal morphine with systemic morphine or buprenorphine, administered in a wide range of antinociceptive doses. The study was performed on Sprague-Dawley rats by using a plantar stimulation test and isobolographic and fractional analyses of drug interaction. The isobolographic and fractional analyses demonstrated that intrathecal morphine interacted with subcutaneous morphine in a synergistic manner while producing a 50% or 75% antinociceptive effect. The sum of D75 fractions was more than that for 50% antinociception, suggesting a less dramatic interaction. The combination with a maximal relative dose of systemic morphine (0.66:1) showed a maximal degree of supraadditivity. The interaction between spinal morphine and systemic buprenorphine was similar to that of morphine/morphine, although the supra-additivity was not as pronounced. For the doses that produced a 50% antinociceptive effect, a synergistic interaction was observed only for the combination with a morphine/buprenorphine ratio of 1.33:1. When the relative amount of intrathecal morphine was decreased or increased, the effect became additive. At the doses that produced 75% antinociception, both combinations of morphine and buprenorphine demonstrated supraadditive interaction.

Rapid reversal of endothelin-1-induced cerebral vasoconstriction by intrathecal administration of nitric oxide donors

OBJECTIVE To determine the capability of donors of nitric oxide (NO) (sodium nitroprusside, nitroglycerine) to reverse endothelin-1 (ET-1)-induced cerebral vasoconstriction in vivo, when administered through the cerebrospinal fluid (CSF) to the adventitial side of the constricted blood vessel. METHODS The rabbit basilar artery was exposed through a transcervical, transclival approach and subsequently subjected to pharmacological manipulations and direct observation of effects by videomicroscopy. Specific manipulations were suffusion of ET-1 (100 nmol/L, 1 ml/min) in synthetic CSF (sCSF) to provoke vasoconstriction and then either suffusion of an NO donor in sCSF (2 mg/ml/min), or sCSF alone. The second suffusion was always made separately and begun during the period of stable maximal vasoconstriction, which occurred between 20 and 30 minutes after beginning the first suffusion. Measurements of the diameter of the artery were made using an inline video caliper. RESULTS Sodium nitroprusside and nitroglycerine, both donors of NO, rapidly and completely reversed ET-1-induced vasoconstriction without causing hypotension. The average value for maximal vasoconstriction by ET-1/sCSF was 50.4% of baseline arterial diameter and occurred between 20 and 30 minutes. The rate of vasodilatory response was 100% of significantly constricted arteries. The response was complete in less than 6 minutes in all preparations, as compared to the 60 minutes required for spontaneous relaxation (sCSF suffusion alone). CONCLUSION NO donors are effective in reversing cerebral vasoconstriction when administered intrathecally, cause no significant hemodynamic change when so administered, and may represent an important therapeutic intervention for cerebral vasospasm.

Antinociceptive effect induced by the combined administration of spinal morphine and systemic buprenorphine.

We evaluated the antinociceptive effect of combined spinal administration of morphine and systemic administration of buprenorphine.Experiments were performed on male Wistar rats. Nociception was measured using the tail immersion test. Buprenorphine was injected intraperitoneally (IP) and morphine was injected intrathecally (IT) via a catheter implanted in the subarachnoid space. Interaction of drugs was analyzed using a dose addition model. Both IT (1-5 [micro sign]g) morphine and IP (50-500 [micro sign]g/kg) buprenorphine increased the latencies of nociceptive responses in a dose-dependent manner. IT morphine (4 [micro sign]g) and IP buprenorphine (100 [micro sign]g/kg) produced 62.9 +/- 6.3 and 48.8 +/- 6.6 percent of the maximal possible effect (%MPE), respectively. The combined administration of 2 [micro sign]g of IT morphine and 50 [micro sign]g/kg IP buprenorphine produced a %MPE of 97.1 +/- 3.4. The analysis of drug interaction revealed that IT morphine interacted with IP buprenorphine in a supraadditive manner while producing a potent antinociceptive effect. Implications: The concurrent administration of spinal morphine and systemic buprenorphine produces an antinociceptive effect that is greater than what could have been predicted from individual dose-response curves. This mode of interaction allows maintenance at a significant level of analgesia with reduced doses of opioids, which minimizes the incidence of undesirable side effects. (Anesth Analg 1998;87:583-6)

Antinociception induced by simultaneous intrathecal and intraperitoneal administration of low doses of morphine

The application of morphine simultaneously into the spinal cord and brain ventricles produces a supraadditive antinociceptive effect.In this study, we attempted to determine whether combined intrathecal (IT) and intraperitoneal (IP) administration of small doses of morphine also produces such a synergistic antinociceptive effect. The experiments were performed on male Wistar rats. Nociception was measured using the tail immersion test. For IT administration morphine was injected through a catheter implanted in the subarachnoid space. Combined administration of small doses of IT (1 micro gram) and IP (1 mg/kg) morphine resulted in a strong, highly significant antinociceptive effect. This effect was not only much higher than that produced by separate administration of the same doses of morphine, but also much higher than the expected effect of the combination. These results demonstrate that low doses of IT and IP morphine interact in a supraadditive fashion to produce potent analgesia. (Anesth Analg 1995;80:886-9)