Anesthesia and analgesia
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Anesthesia and analgesia · Apr 2014
Differential suppression of intracranial self-stimulation, food-maintained operant responding, and open field activity by paw incision and spinal nerve ligation in rats.
Detection of ongoing spontaneous pain behaviors in laboratory animals remains a research challenge. Most preclinical pain studies measure elicited behavioral responses to an external noxious stimulus; however, ongoing spontaneous pain in humans and animals may be unrelated to hypersensitivity, and likely diminishes many behaviors, particularly motivated behaviors, that we hypothesize will decrease after induction of acute and chronic pain. ⋯ The acute effects of INC on decreasing lever pressing for VTA ICSS and FR (1-2 days after incision) correspond to the timeframe in which ongoing spontaneous pain is expected to occur after INC. Therefore, these decreases are likely mediated by ongoing spontaneous pain, which may be unrelated to mechanical hypersensitivity that persists for up to 4 days after INC. PWT is decreased similarly by SNL, yet operant behavior (lever pressing for VTA ICSS and FR) was not decreased by SNL. SNL, but not INC, decreased rearing behavior but not total distance traveled during OFA. This further indicates that the presence and the extent of hypersensitivity are not predictive of many behavioral changes in rats thought to be mediated by the presence of ongoing pain. Surprisingly, the behavioral effects of INC are not exacerbated in SNL rats. These data support the growing belief that acute pain models produce short-lived spontaneous pain behaviors that are often less pronounced or absent in neuropathic pain models, and highlight the need for assessment of both evoked and nonevoked pain behaviors in developing future therapies for acute and chronic pain.
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Anesthesia and analgesia · Apr 2014
An improved design of water-soluble propofol prodrugs characterized by rapid onset of action.
Phosphate ester prodrugs of propofol (fospropofol, HX0969W) were designed to avoid the unsatisfactory water solubility of the parent drug. However, in previous clinical trials, there were reported prodrug side effects such as paresthesia and pruritus. The accumulation of a phosphate ester component was found to be the main culprit. To exclude this potential risk, we designed 2 amino acid propofol prodrugs (HX0969-Gly-F3, HX0969-Ala-HCl) based on the lead compound (HX0969) by introducing the amino acid group into the structures of the propofol prodrugs. We hypothesized that the improved propofol prodrugs could not only eliminate those adverse effects but also retain their rapid action and good water solubility. ⋯ Application of the amino acid group to the propofol prodrug can make the prodrug have good water solubility and a more rapid onset of action. In rat plasma, the 2 improved amino acid prodrugs (HX0969-Ala-HCl, HX0969-Gly-F3) had a more rapid rate of propofol release than the 2 phosphate ester prodrugs (fospropofol, HX0969W). The in vivo tests showed that HX0969-Ala-HCl and HX0969-Gly-F3 given IV could have a more rapid onset of action in a smaller dose than fospropofol and HX0969W. This novel design can enhance the efficiency of prodrugs converting to propofol.
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Anesthesia and analgesia · Apr 2014
Topical combinations to treat microvascular dysfunction of chronic postischemia pain.
Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle, and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain. ⋯ The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS.