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Objective(s): The relationship between tramadol, as an antinociceptive drug, and locus coeruleus (LC), the main noradrenergic nucleus of the brain that affects regulation and modulation of pain through descending noradrenergic pathways was investigated. Materials and Methods: Male Sprague-Dawley rats were divided into four groups of 10 rats. The rats were fixed in stereotaxic instrument and then a probe was inserted into LC. Pain was induced by subcutaneous injection of 50 μl of 2.5% formalin 40 minutes after initiation of microdialysis in right hind paw, and nociceptive pain scores were calculated every 5 minutes. Subsequently noradrenaline (NA) and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were collected and measured by microdialysis of locus coeruleus in freely moving rats every 15 minutes during formalin injection. Results: Nociceptive pain scores observed in formalin test had the highest nociceptive sensation 5 minutes after injection. Significant rises in concentrations of NA and MHPG, in samples taken between 30 and 45 min after initiation of the locus coeruleus microdialysis, coincided with the peak of the pain after injection of formalin. Conclusion: According to concurrency of the highest nociceptive sensation and peak of NE and MHPG concentrations, tramadol can indirectly affect the LC by blocking the pain signals from different parts of the brain such as periaqueductal gray mater, central nucleus of amygdale or the spinal cord.

The effects of tramadol on norepinephrine and MHPG releasing in locus coeruleus in formalin test in rats: a brain stereotaxic study