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This study aims to investigate the effect of Mygalin, an acylpolyamine synthesized from a natural molecule in the hemolymph of the <jats:italic>Acanthoscurria gomesiana<\/jats:italic> spider, injected into the prelimbic (PrL) region of the medial prefrontal cortex on chronic neuropathic pain and depression comorbidity in rats. To investigate that comorbidity, neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in male Wistar rats. The biotinylated biodextran amine (BDA) bidirectional neural tract tracer was microinjected into the PrL cortex to study brain connections. Rodents were further subjected to von Frey (mechanical allodynia), acetone (cold allodynia), and forced swim (depressive\u2010like behavior) tests. BDA neural tract tracer\u2010labeled perikarya were found in the dorsal columns of the periaqueductal gray matter (dPAG) and the dorsal raphe nucleus (DRN). Neuronal activity of DRN neurons decreased in CCI rats. However, PrL cortex treatment with Mygalin increased the number of spikes on DRN neurons. Mygalin treatment in the PrL cortex decreased both mechanical and cold allodynia and immobility behavior in CCI rats. PrL cortex treatment with N\u2010methyl\u2010<jats:sc>D<\/jats:sc>\u2010aspartate (NMDA) receptor receptors attenuated the analgesic and antidepressive effects caused by Mygalin. The PrL cortex is connected with the dPAG and DRN, and Mygalin administration into the PrL increased the activity of DRN neurons. Mygalin in the PrL cortex produced antinociceptive and antidepressive\u2010like effects, and the NMDA agonist reversed these effects.<\/jats:p>","DOI":"10.1002\/jbt.23353","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T05:16:03Z","timestamp":1681794963000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<i>Acanthoscurria gomesiana<\/i> spider\u2010derived Mygalin in the prelimbic prefrontal cortex modulates neuropathic pain and depression comorbid"],"prefix":"10.1002","volume":"37","author":[{"given":"Ana Carolina","family":"Medeiros","sequence":"first","affiliation":[{"name":"Department of Surgery and Anatomy Ribeir\u00e3o Preto Medical School of the University of S\u00e3o Paulo (FMRP\u2010USP),\u00a0Multi\u2010User Center of Neuroelectrophysiology Ribeir\u00e3o Preto S\u00e3o Paulo Brazil"},{"name":"Laboratory of Neuroscience of Pain &amp; Emotions, Department of Surgery 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