European journal of pharmacology
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Comparative Study
Human cyclooxygenase-1b is not the elusive target of acetaminophen.
A cyclooxygenase-1 splice variant (cyclooxygenase-1b), cloned from canine brain, was proposed to be an acetaminophen-sensitive enzyme. Unlike in canines, the retention of intron 1 in the human sequence results in a frame shift and predicts a truncation of the protein. ⋯ Human cyclooxygenase-1bDeltaG was active but was not inhibited by acetaminophen. In conclusion, full length human cyclooxygenase-1b is clearly not the target of acetaminophen.
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Descending noradrenergic pathways contribute to feedback inhibition of pain by releasing norepinephrine in the spinal cord. Noradrenergic nuclei in the pons contain abundant alpha(2)-adrenoceptors. We assessed the contribution of pontine alpha(2)-adrenoceptors to endogenous regulation of pain in nerve-injured rats. ⋯ Suppression of heat nociception in uninjured dermatomes of nerve-injured but not the control animals following i.t. administration of atipamezole indicates that nerve injury produced a tonic activation of noradrenergic feedback inhibition acting on spinal alpha(2)-adrenoceptors. In parallel, antiallodynia induced by pontine administration of atipamezole indicates that nerve injury induces a tonic activation of pontine alpha(2)-adrenoceptors that promotes neuropathic hypersensitivity by attenuating descending inhibition. Thus, spinal and pontine alpha(2)-adrenoceptors have opposite effects on pain-related behavior in neuropathic animals.
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The analgesic effects of opioid agonists and the expression of mu- and kappa-opioid receptors were compared between mice with herpetic pain and those with postherpetic pain induced by herpetic virus inoculation. Morphine inhibited herpetic pain more effectively than postherpetic pain. Intrathecal injection reduced the analgesic effects of morphine on postherpetic pain, but intracerebroventricular injection did not. ⋯ In the dorsal root ganglia, the expression of mu-opioid receptor mRNA was significantly decreased in mice with postherpetic pain, whereas the kappa-opioid receptor mRNA level was not altered. These results suggest that specific down-regulation of the mu-opioid receptor in the primary sensory neurons is responsible for the reduced analgesic action of morphine on postherpetic pain. The kappa-opioid receptor may be a useful target for the analgesic treatment of postherpetic neuralgia.
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We profiled changes in gene expression in the hippocampus 2 days after a 4 h general anesthetic with isoflurane and nitrous oxide. Eighteen month old Fisher 344 rats were anesthetized for 4 h with 1.2% isoflurane and 70% nitrous oxide (N=9) whereas control rats breathed 30% oxygen for 4 h (N=9). Rats were sacrificed 48 h later and RNA extracted from the hippocampus for gene expression profiling. ⋯ The majority of differentially expressed genes are implicated in cell stress and replication, signal transduction, transcription, protein biosynthesis, cell structure, and metabolism. The correlation between fold changes on array and reverse transcriptase polymerase chain reaction was good (R2=0.85) for the 6 genes examined with both methods. These results demonstrate that in rats general anesthesia is associated with persistent changes in hippocampal gene expression, suggesting that recovery of the brain from anesthesia is considerably slower than generally recognized.
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The present study was aimed to elucidate the possible role of Na+ -K+ -2Cl- -cotransporter (NKCC1) on traumatic brain injury-induced brain edema, cerebral contusion and neuronal death by using traumatic brain injury animal model. Contusion volume was verified by 2,3,5,-triphenyltetrazolium chloride monohydrate staining. NKCC1 mRNA expression was detected by RT-PCR and the protein expression of NKCC1 was measured by Western blot. ⋯ Administration of the NKCC1 inhibitor bumetanide (15 mg/kg, I. V.) significantly attenuated the contusion volume (464.03 +/- 23.62 mm3) and brain edema (water content: 79.12 +/- 0.28%) after traumatic brain injury. Our study demonstrates that NKCC1 contributes to traumatic brain injury-induced brain edema and neuronal damage.