Abstract
The mu opioid receptor (MOR) is critical in mediating morphine analgesia. However, prolonged exposure to morphine induces adaptive changes in this receptor leading to the development of tolerance and addiction. In the present work we have studied whether the continuous administration of morphine induces changes in MOR protein levels, its pharmacological profile, and MOR-mediated G-protein activation in the striosomal compartment of the rat CPu, by using immunohistochemistry and receptor and DAMGO-stimulated [35S]GTPγS autoradiography. MOR immunoreactivity, agonist binding density and its coupling to G proteins are up-regulated in the striosomes by continuous morphine treatment in the absence of changes in enkephalin and dynorphin mRNA levels. In addition, co-treatment of morphine with the dopamine D4 receptor (D4R) agonist PD168,077 fully counteracts these adaptive changes in MOR, in spite of the fact that continuous PD168,077 treatment increases the [3H]DAMGO Bmax values to the same degree as seen after continuous morphine treatment. Thus, in spite of the fact that both receptors can be coupled to Gi/0 protein, the present results give support for the existence of antagonistic functional D4R-MOR receptor-receptor interactions in the adaptive changes occurring in MOR of striosomes on continuous administration of morphine.
Highlights
The opioid morphine is one of the most potent analgesic drugs used to relieve moderate to severe pain [1]
We have studied the effect of D4 receptor (D4R) activation on mu opioid receptor (MOR) changes induced by morphine in the rat caudate putamen (CPu) on a continuous drug treatment paradigm, by analyzing MOR protein level, pharmacological profile, and functional coupling to G proteins
Levels of MOR protein expression were determined in the rat CPu after six days of continuous administration of morphine (20 mg/kg/day)
Summary
The opioid morphine is one of the most potent analgesic drugs used to relieve moderate to severe pain [1]. Morphine research has long been focused on the development of analogs, or drug administration strategies, which could result in an effective analgesic therapy without side effects. Opioids exert their pharmacological actions through their interactions with the opioid receptors μ (MOR), δ (DOR), and κ (KOR), which belong to the family of G protein-coupled receptors (GPCRs) [4]. The existence of MOR-DOR and MOR-KOR heteromers has been demonstrated in the central nervous system (CNS) to integrate antinociceptive signals, having a role in the addictive effect of opioids, such as morphine [11,12,13]. The endogenous opioids enkephalin (Enk) and dynorphin (Dyn), as the main ligands of these receptors in the CPu, can contribute to receptor regulation and downstream signaling processes [14]
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