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Background: Antidepressants are the first-choice for pharmacological treatment of panic disorder. However, they present disadvantages, such as delayed therapeutic effect, many side effects and a considerable rate of non-responders. These shortcomings prompt the development of new therapeutic strategies. Among these are the adjunctive use of enkephalinase inhibitors, such as opiorphin, which supposedly acts by increasing the availability of brain enkephalins and other endogenous opioids., Aims: We here evaluated whether opiorphin in the dorsal periaqueductal grey matter (dPAG), a key panic-related area, accelerates and/or facilitates the antipanic-like effect of fluoxetine or imipramine. We also verified whether the panicolytic effect of imipramine depends on activation of μ-opioid receptors (MORs)., Methods: Male Wistar rats were submitted to the escape task of the elevated T-maze, an index of panic attack, after treatment with imipramine (3, 7 or 21 days) or fluoxetine (3, 7, 14 or 21 days), combined with an intra-dPAG injection of opiorphin., Results: Opiorphin facilitated and accelerated the panicolytic-like effect caused by imipramine, but not with fluoxetine. The antipanic-like effect caused by chronic imipramine did not depend on MOR activation in the dPAG., Conclusion: Combined treatment of antidepressant drugs with opiorphin for hastening or potentiating the effects of the former compounds may not be generally effective, with the results varying depending on the type/class of these panicolytic drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Reported results have shown that the pentapeptide opiorphin inhibits oligopeptidases that degrade brain neuropeptides, and has analgesic and antidepressant effects in experimental animals, without either tolerance or dependency after chronic administration. In a previous study we showed that opiorphin has a panicolytic-like effect in the dorsal periaqueductal gray (dPAG) electrical stimulation test (EST), mediated by the μ-opioid receptor (MOR). This study further analyzes the mechanism of opiorphin panicolytic action, using the EST and drug injection inside the dPAG. The obtained results showed that blockade of the 5-HT 1A receptors with WAY-100635 did not change the escape-impairing effect of opiorphin, and combined injection of sub-effective doses of opiorphin and the 5-HT 1A -agonist 8-OH-DPAT did not have a significant anti-escape effect. In contrast, the anti-escape effect of opiorphin was antagonized by pretreatment with the kinin B2 receptor blocker HOE-140, and association of sub-effective doses of opiorphin and bradykinin caused a significant anti-escape effect. The anti-escape effect of bradykinin was not affected by previous administration of WAY-100635. Therefore, the anti-escape effect of opiorphin in the dPAG seems to be mediated by endogenous bradykinin, acting on kinin B2 receptors, which previous results have shown to interact synergistically with MOR in the dPAG to restrain escape in two animal models of panic. Chemical compounds: Opiorphin (PubChem CID: 25195667); WAY100635 maleate salt (PubChem CID: 11957721); 8-OH-DPAT hydrobromide (PubChem CID: 6917794); Bradykinin (PubChem CID: 439201); HOE-140 (Icatibant) (PubChem CID: 6918173)., (Copyright © 2017 Elsevier Inc. All rights reserved.)