Abstract
Opioids, acting at μ opioid receptors, are commonly used for pain management. Chronic opioid treatment induces cellular adaptations, which trigger long-term side effects, including constipation mediated by enteric neurons. We tested the hypothesis that chronic opioid treatment induces alterations of μ opioid receptor signaling in enteric neurons, which are likely to serve as mechanisms underlying opioid-induced constipation. In cultured rat enteric neurons, either untreated (naïve) or exposed to morphine for 4 days (chronic), we compared the effect of morphine and DAMGO (D-Ala2,MePhe4,Gly-ol5 enkephalin) on μ opioid receptor internalization and downstream signaling by examining the activation of the mitogen-activated protein kinase/extracellular signal-regulated kinases 1 and 2 (MAPK/ERK) pathway, cAMP accumulation and transcription factor cAMP Response Element-Binding protein (CREB) expression. μ opioid receptor internalization and MAPK/ERK phosphorylation were induced by DAMGO, but not morphine in naïve neurons, and by both opioids in chronic neurons. MAPK/ERK activation was prevented by the receptor antagonist naloxone, by blocking receptor trafficking with hypertonic sucrose, dynamin inhibitor, or neuronal transfection with mutated dynamin, and by MAPK inhibitor. Morphine and DAMGO inhibited cAMP in naïve and chronic enteric neurons, and induced desensitization of cAMP signaling. Chronic morphine treatment suppressed desensitization of cAMP and MAPK signaling, increased CREB phosphorylation through a MAPK/ERK pathway and induced delays of gastrointestinal transit, which was prevented by MAPK/ERK blockade. This study showed that opioids induce endocytosis- and dynamin-dependent MAPK/ERK activation in enteric neurons and that chronic morphine treatment triggers changes at the receptor level and downstream signaling resulting in MAPK/ERK-dependent CREB activation. Blockade of this signaling pathway prevents the development of gastrointestinal motility impairment induced by chronic morphine treatment. These findings suggest that alterations in μ opioid receptor downstream signaling including MAPK/ERK pathway in enteric neurons chronically treated with morphine contribute to the development of opioid-induced constipation.
Highlights
The long-term use of opioids for the treatment of moderate to severe pain is a common clinical practice and has increased exponentially during the past decade in the United States [1]
This study showed that opioids induce activation of mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase 1 and 2 (ERK1/2) in enteric neurons of the small intestine through a pathway requiring mOR internalization, whereas opioid inhibition of cAMP signaling is independent of ligand internalization efficiency
Chronic morphine treatment suppressed opioidinduced desensitization of cAMP and MAPK signaling and induced activation of the transcription factor, cAMP Response Element-Binding protein (CREB) through a MAPK/ERK pathway, since it was prevented by a selective MEK inhibitor, an upstream protein of ERK
Summary
The long-term use of opioids for the treatment of moderate to severe pain is a common clinical practice and has increased exponentially during the past decade in the United States [1] Opioid drugs exert their pharmacological effects by interacting with the opioid receptors (ORs), mostly targeting the mORs. Binding of opioids with mORs in neurons of the central nervous system (CNS) induces analgesia, whereas activation of mORs in neurons of the enteric nervous system (ENS) inhibits gastrointestinal (GI) motility and secretion [2,3,4,5]. Internalization and desensitization are critical events regulating downstream signaling and receptor function, and alteration of these regulatory processes induced by long-term opioid treatment results in intracellular adaptations underlying the development of opioid-induced side effects [6]. Blockade of MAPK/ERK pathway reversed the delay of GI transit induced by chronic morphine These findings support the concept that changes in mOR downstream signaling in enteric neurons induced by chronic morphine treatment are important factors underlying the development of long-term GI opioid effects
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