The role of the adrenergic system and HPA axis in protective effects of morphine against PTSD-like symptoms in rats

Background and Aim : Post-traumatic stress disorder (PTSD) arises after tremendous traumatic experiences. Recently, we showed that morphine has time-dependent protective effects against behavioral and morphological deficits in the single prolonged stress (SPS) as an experimental model of PTSD in adult male rats. To find the mechanisms underlying the protective effects of morphine against SPS-induced PTSD-like symptoms, we investigated the interaction between morphine and sympathetic nervous system (SNS) as well as hypothalamic-pituitary-adrenal (HPA) axis which crucially involved in stress response.Methods : The animals were exposed to the SPS (restraint for 2 h, forced swimming for 20 min, and ether anesthesia) and morphine or saline was injected 24 hours after the SPS. Pharmaceutical interventions were administered 30 to 90 minutes before morphine/saline injection. Anxiety-like behaviors were evaluated using the elevated plus maze (EPM) 11 days after the SPS. After that, animals were conditioned in a fear conditioning task and extinction training was performed on days 1, 2, 3, 4 and 11 after fear conditioning.Results : (1) Blockade of glucocorticoid receptors by RU-486 90 minutes before morphine injection, prevented the protective effects of morphine, reduced extinction index, increased freezing time and anxiety-like behaviors, (2) blockade of mineralocorticoid receptors by spironolactone 90 minutes before morphine injection, prevented the protective effects of morphine on SPS-induced anxiety-like behaviors, increased freezing time and reduced extinction index, (3) corticosterone synthesis inhibition by metyrapone 90 minutes before morphine injection, prevented the protective effects of morphine, reduced extinction index, increased freezing time and anxiety-like behaviors, (4) regarding SPS-induced anxiety-like behaviors, blockade of beta-adrenoceptors by propranolol 30 minutes before morphine or saline injection, not only did not affect the protective effects of morphine, but also decreased anxiety-like behaviors in the saline-treated SPS rats. In terms of fear extinction, however, propranolol prevented the protective effects of morphine, increased freezing time and reduced extinction index, (5) blockade of peripheral beta-adrenoceptors by nadolol 30 minutes before morphine injection did not affect the protective effects of morphine on SPS-induced anxiety-like behaviors, freezing time and extinction index, (6) blockade of alpha-2 adrenoceptors by yohimbine, and enhancing the release of norepinephrine, 30 minutes before morphine injection, did not affect the protective effects of morphine on SPS-induced anxiety-like behaviors, but in terms of fear extinction, yohimbine prevented the protective effects of morphine and increased freezing time. Interestingly, yohimbine reduced freezing time in the saline-treated SPS rats.Conclusion : The protective effects of morphine on PTSD-like symptoms in rats require a certain level of HPA axis and SNS activity and any alteration in the function of their hormones can lead to the vanishing of the protective effects of morphine. Glucocorticoid and mineralocorticoid receptors, as well as, alfa-2 and central but not peripheral beta-adrenoceptors are involved in these effects. Moreover, beta-adrenoceptors blockade by propranolol, at least 24 hours after the SPS, not only had no beneficial effect on SPS-induced fear extinction impairment, but also SNS stimulation improved fear extinction. Indeed, the implementation of preventive pharmaceutical interventions after the traumatic events to prevent PTSD is not so straightforward than previously thought and further investigation is needed.

کلیدواژه ها:

PTSD ، SPS ، Morphine ، Extinction ، HPA axis ، SNS