Morphine Withdrawal Activates Hypothalamic-Pituitary-Adrenal Axis and Heat Shock Protein 27 in the Left Ventricle: The Role of Extracellular Signal-Regulated Kinase

Abstract

The negative affective states of withdrawal involve the recruitment of brain and peripheral stress circuitry [e.g., noradrenergic activity, induction of the hypothalamo-pituitary-adrenocortical (HPA) axis, and the expression and activation of heat shock proteins (Hsps)]. The present study investigated the role of extracellular signal-regulated protein kinase (ERK) and ␤-adrenoceptor on the response of stress systems to morphine withdrawal by the administration of [amino[(4-aminophenyl)thio] methylene]-2-(trifluoromethyl)benzeneacetonitrile (SL327), a selective inhibitor of ERK activation, or propranolol (a ␤-adrenoceptor antagonist). Dependence on morphine was induced by a 7-day subcutaneous implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by the injection of naloxone (2 mg/kg s.c.). Plasma concentrations of adrenocorticotropin and corticosterone were determined by radioimmunoassay; noradrenaline (NA) turnover in left ventricle was determined by high-performance liquid chromatography; and catechol-O-methyl transferase (COMT) and Hsp27 expression and phosphorylation at Ser82 were determined by quantitative blot immunolabeling. Morphine-withdrawn rats showed an increase of NA turnover and COMT expression in parallel with an enhancement of adrenocorticotropin and plasma corticosterone concentrations. In addition, we observed an enhancement of Hsp27 expression and phosphorylation. Pretreatment with SL327 or propranolol significantly reduced morphine withdrawal-induced increases of plasma adrenocorticotropin and Hsp27 phosphorylation at Ser82 without any changes in plasma corticosterone levels. The present findings demonstrate that morphine withdrawal is capable of inducing the activation of HPA axis in parallel with an enhancement of Hsp27 expression and Hsp27 phosphorylation at Ser82 and suggest a role for ␤-adrenoceptors and ERK pathways in mediating morphine-withdrawal activation of the HPA axis and cellular stress response.

Corticotropin‐releasing factor (CRF) receptor‐1 is involved in cardiac noradrenergic activity observed during naloxone‐precipitated morphine withdrawal

“…However, COMT activity has repeatedly been suggested to be associated with increased vulnerability to the development of drugs abuse (Li et al ., ; Beuten et al ., ; Ersche et al ., ) and reward processing (Tunbridge et al ., ), but there are few data about its role during morphine withdrawal (Martínez‐Laoden et al ., ). The present results demonstrated that naloxone‐precipitated morphine withdrawal caused a decrease in myocardial NA levels and increases in myocardial NMN (extraneuronal NA metabolite generated by COMT), in parallel with an increased expression of MB‐COMT and S‐COMT, suggesting that both isoforms of COMT are implicated in the degradation of NA.…”

“…As the repeated exposure to morphine and its withdrawal induces profound and severe stress reactions that are also evidenced by over expression of Hsp27 (Almela et al ., ; Drastichova et al ., ; Martínez‐Laoden et al ., ), we evaluated Hsp27 expression and phosphorylation in the left ventricle in wild‐type and CRF 1 receptor knockout mice. In accord with previous data (Almela et al ., ; Drastichova et al ., ; Martínez‐Laoden et al ., ), the present investigation showed that both chronic morphine treatment and its withdrawal are associated with an increase of Hsp27 expression. However, chronic morphine treatment did not modify Hsp27 phosphorylation, whereas naloxone administration to morphine‐treated rats induced an enhancement of Hsp27 phosphorylation at Ser 82 .…”

The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence

“…Given that conditions of chronic stress have been shown to significantly increase microglial activation, it suggests that repeated withdrawal may have acted as a chronic stressor [32]. Certainly, withdrawal from chronic opioids has been shown to elevate hypothalamic-pituitary-adrenal axis signaling, lending support to this hypothesis [33][34][35][36]. Additional studies are warranted to explore whether these different morphine treatment regimens impact other behaviors such as locomotion, anxiety, and depression.…”

Pharmacological induction of CCL5 in vivo prevents gp120-mediated neuronal injury

“…For instance, morphine withdrawal has been shown to increase the number of microglia cells as well as pro-inflammatory cytokines such as IL-1β and TNF-α (Campbell et al, 2013) that promote caspase-8 and -3 dependent apoptosis (Emeterio et al, 2006). Opioid withdrawal also increases the levels of corticosteroids (Martínez-Laorden et al, 2012) which are known to enhance gp120 toxicity (Brooke and Sapolsky, 2002). Moreover, a recent study suggested that opioid withdrawal may accelerate progression to HIV-associated neurocognitive disorders by increasing ceramide (Bandaru et al, 2011), a sphingolipid that negatively regulates synaptic function.…”