Anesthesia and analgesia
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Anesthesia and analgesia · May 2004
The monoamine reuptake inhibitor milnacipran does not affect nociception to acute visceral distension in rats.
The role of antidepressants in the treatment of visceral pain has not been extensively examined. Milnacipran, an antidepressant that inhibits monoamine reuptake, is widely used in the treatment of depression and fibromyalgia. In this study, we sought to determine the activity of milnacipran against acute visceral nociception. Female virgin rats were studied 7 days after bilateral ovariectomy. For uterine cervical distension (UCD), two metal rods were inserted into the cervical osses under general anesthesia for manual distension. Colorectal distension (CRD) was performed by insertion of a balloon catheter into the descending colon and rectum, followed by manual inflation. Two electrodes were inserted into the rectus abdominus muscle for recording UCD- or CRD-induced reflex contraction, which was quantified by electromyography (EMG). A dose response for milnacipran, administered intrathecally or i.v., was obtained for UCD and CRD stimulation. Milnacipran failed to inhibit the UCD-induced EMG response, whether administered i.v. or intrathecally. Similarly, i.v. milnacipran, administered either acutely or chronically, failed to inhibit the CRD-induced EMG response. CRD and UCD are well established animal models for the study of acute visceral pain. Milnacipran, although it provides some unique advantages compared with other antidepressants, is unlikely to produce analgesia after acute administration in the setting of acute visceral pain. ⋯ Neither intrathecal nor i.v. milnacipran, a monoamine reuptake inhibitor, inhibits an acute visceral pain response induced by colorectal or uterine cervical distension.
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Anesthesia and analgesia · May 2004
Characteristic of interactions between intrathecal gabapentin and either clonidine or neostigmine in the formalin test.
Intrathecal gabapentin is effective for phase 2 of the formalin response but not for acute pain. Unlike gabapentin, intrathecal clonidine and neostigmine attenuate both acute pain and phase 2 of the formalin response. We evaluated gabapentin's interactions with either clonidine or neostigmine in the formalin test. Male Sprague-Dawley rats were used. For the formalin test, 50 microL of 5% formalin solution was injected into the hindpaw. The interaction of drugs was investigated by a fixed-dose analysis or an isobolographic analysis. Intrathecal gabapentin produced a suppression of the phase 2 flinching response, but not the phase 1 response, in the formalin test. Intrathecal clonidine and neostigmine resulted in a reduction of the pain behavior in both phases. A fixed-dose analysis in phase 1 showed that gabapentin potentiated the antinociceptive effect of clonidine and neostigmine. An isobolographic analysis in phase 2 revealed a synergistic interaction after intrathecal administration of gabapentin-clonidine or gabapentin-neostigmine mixture. We conclude that the combination of gabapentin with either clonidine or neostigmine at the level of the spinal cord could play a major role not only in acute pain, but also in phase 2 of the formalin response. ⋯ We determined the pharmacological properties of gabapentin combined with either clonidine or neostigmine in the formalin test. Spinal gabapentin reinforced the effects of clonidine and neostigmine in the formalin test. The hitherto unreported action of gabapentin on acute nociceptive stimulus could be of considerable significance.
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Anesthesia and analgesia · May 2004
Metoclopramide causes airway smooth muscle relaxation through inhibition of muscarinic M3 receptor in the rat trachea.
Although metoclopramide, often used as an antiemetic, is reported to have an anticholinesterase action, the effect on airway smooth muscle remains unclear. We investigated the effect of metoclopramide on the contraction, phosphatidylinositol response, and binding affinity of muscarinic M(3) receptors in rat trachea preparations. Male Wistar rats were anesthetized and their tracheas excised and chopped into 3-mm-wide rings, 1-mm-wide slices, or frozen 10- microm-thick sections. Contraction was induced with 0.55 microM carbachol (CCh) and, 30 min later, metoclopramide (10 microM to 1 mM) was added. The slices were incubated with (3)[H]myo-inositol, 0.55 microM CCh, and metoclopramide, and the formation of (3)[H] inositol monophosphate was measured. A radioligand binding study was conducted to examine the effects of metoclopramide using [(3)H] 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP), a muscarinic M(3) receptor antagonist, in sections of the trachea. Metoclopramide concentration dependently attenuated CCh-induced contraction and inositol monophosphate accumulation, and also attenuated the binding affinity of 4-DAMP to muscarinic M(3) receptors. The 50% inhibitory concentration of metoclopramide against the binding affinity of 4-DAMP to muscarinic M(3) receptors of rat trachea was 24 micro M. These findings suggest that the attenuation by metoclopramide of CCh-induced contraction and phosphatidylinositol response may be mediated through the muscarinic M(3) receptors. ⋯ We investigated the effect of metoclopramide on the contraction, phosphatidylinositol response, and binding affinity of muscarinic M(3) receptors in rat trachea preparations. Our findings suggest that the attenuation by metoclopramide of carbachol-induced contraction and phosphatidylinositol response may be mediated through the muscarinic M(3) receptors.
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Anesthesia and analgesia · May 2004
Rapid skin anesthesia using a new topical amethocaine formulation: a preclinical study.
We developed a fast-acting topical amethocaine emulsion and tested its analgesic activity against heat or mechanically induced pain in a rat paw model. The first experiment was performed in rats made hyperalgesic or allodynic after carrageenan-induced inflammation. Rats were distributed in five subgroups, each receiving topically one of the following: amethocaine microemulsion, amethocaine gel (Ametopgel), EMLA (Eutectic Mixture of Local Anesthetics) cream, amethocaine infiltration, or nothing (controls). The second experiment was conducted on healthy, selected heat- or touch-hypersensitive rats, which were distributed as in the first experiment. Paw withdrawal time from a heat and a mechanical stimulus was used as a pain index. In the first experiment, antihyperalgesic activity appeared at 4.2, 13.8, and 14 min after amethocaine microemulsion, gel, or EMLA cream, respectively. Amethocaine microemulsion was the only topical formulation with an antiallodynic effects, although less than with amethocaine infiltration. In healthy rats (second experiment), all topical formulations produced similar analgesic effects in heat-induced pain of the ipsilateral paw. Activity in the contralateral paw appeared earlier with amethocaine microemulsion, which was also the only one that increased touch-induced withdrawal time in the ipsi- and contralateral paws. Therefore, the microemulsion could be valuable for improving amethocaine skin penetration and thus bringing rapid pain relief. ⋯ Topical anesthetics are used in several painful clinical procedures, but they tend to have a slow onset time. A new amethocaine microemulsion with a faster onset of analgesia than commercial formulations was developed and its activity tested in pain states induced by heat or mechanical stimulus in inflamed and healthy rat paws.