Abstract
G protein-coupled receptors (GPCRs) comprise a large family of membrane receptors involved in signal transduction. These receptors are linked to a variety of physiological and biological processes such as regulation of neurotransmission, growth, and cell differentiation among others. Some of the effects of GPCRs are known to be mediated by the activation of mitogen-activated extracellular kinase (MAPK) pathways. Cross-talk among various signal pathways plays an important role in activation of intracellular and intranuclear signal transduction cascades. Naloxone-induced morphine withdrawal leads to an up-regulation of adenyl cyclase-mediated signaling, resulting in high expression of protein kinase (PK) A. In addition, there is also an increased expression of extracellular signal regulated kinase (ERK), one member of MAPK. For this reason, the crosstalk between these GPCRs and receptors with tyrosine kinase activity (TKR) can be considered a possible mechanism for adaptive changes that occurs after morphine withdrawal. Morphine withdrawal activates ERK1/2 and phosphorylated tyrosine hydroxylase (TH) at Ser31 in the right and left ventricle. When N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004), a PKA inhibitor was infused, the ability of morphine withdrawal to activate ERK, which phosphorylates TH at Ser31, was reduced. The present finding demonstrated that the enhancement of ERK1/2 expression and the phosphorylation state of TH at Ser31 during morphine withdrawal are dependent on PKA and suggest cross-talk between PKA and ERK1/2 transduction pathway mediating morphine withdrawal-induced activation of TH. Increasing understanding of the mechanisms that interconnect the two pathway regulated by GPCRs and TKRs may facilitate the design of new therapeutic strategies.
Highlights
The development of opioid addiction involves complex adaptive changes in opioid receptors and associated signaling systems leading to neuronal plasticity in specific brain regions (Nestler and Aghajanian, 1997; Ueda, 2004)
The injection of naloxone in rats chronically treated with HA-1004, Calphostin C or SL327 concomitantly with morphine induced a weight loss, similar to the group chronically pretreated with vehicle plus morphine (Figure 1C)
Morphine-withdrawn animals treated with vehicle, HA-1004, calfostin C or SL327 displayed characteristic abstinence symptoms: Wet-dog shakes, teeth chattering, ptosis, tremor, piloerection, lacrimation, rhinorrhea, chromodacryorrhea and spontaneous jumping
Summary
The development of opioid addiction involves complex adaptive changes in opioid receptors and associated signaling systems leading to neuronal plasticity in specific brain regions (Nestler and Aghajanian, 1997; Ueda, 2004). In addition to the neurobehavioral consequences of opioid addiction, there is a strong association between drug addiction and cardiac disorders. Various types of cardiac arrhythmias have been described in heroin addicts. Despite the clinical relevance of an association between addiction and cardiovascular disorders, little is known about the pathophysiology or mechanisms underlying this comorbidity. The majority of cardiology studies were oriented on clinical usage of this drug and current cardiovascular research has been limited to the evaluation of factors or pathways believed to contribute to its physiological actions (Jiang et al, 2006; Xu et al, 2011). Investigation about the mechanisms implicated in the cardiac adaptive changes that occur during morphine withdrawal deserves more attention
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