Abstract
Nowadays, pain represents one of the most important societal burdens. Current treatments are, however, too often ineffective and/or accompanied by debilitating unwanted effects for patients dealing with chronic pain. Indeed, the prototypical opioid morphine, as many other strong analgesics, shows harmful unwanted effects including respiratory depression and constipation, and also produces tolerance, physical dependence, and addiction. The urgency to develop novel treatments against pain while minimizing adverse effects is therefore crucial. Over the years, the delta-opioid receptor (DOP) has emerged as a promising target for the development of new pain therapies. Indeed, targeting DOP to treat chronic pain represents a timely alternative to existing drugs, given the weak unwanted effects spectrum of DOP agonists. Here, we review the current knowledge supporting a role for DOP and its agonists for the treatment of pain. More specifically, we will focus on the cellular and subcellular localization of DOP in the nervous system. We will also discuss in further detail the molecular and cellular mechanisms involved in controlling the cellular trafficking of DOP, known to differ significantly from most G protein-coupled receptors. This review article will allow a better understanding of how DOP represents a promising target to develop new treatments for pain management as well as where we stand as of our ability to control its cellular trafficking and cell surface expression.
Highlights
Nowadays, pain represents one of the most important societal burdens
If the distribution of delta-opioid receptor (DOP) in primary afferents and spinal cord neurons remains a matter of debate, its expression in all structures involved in pain processing, as well as its more restricted expression within structures implicated in pain modulation in higher species, raise DOP among the most promising targets for the development of novel pain therapies
DOP represents a promising target for the treatment of pain
Summary
Pain processing runs through a distinctive neurological pathway. The propagation of pain starts with the activation of receptors, called nociceptors, which are found widely in peripheral tissues, muscles, and organs (Almeida et al, 2004). This circuit involves multiple regions of the central nervous system such as the frontal neocortex, the hypothalamus, the amygdala, the rostral anterior cingulate cortex (rAAC), the periaqueductal gray region (PAG), the medulla and the rostroventral medulla (RVM; Fields et al, 2006; Ossipov et al, 2010) This ensemble projects to the dorsal horn of the spinal cord to modulate the ascending pain signal (Fields et al, 2006; Ossipov et al, 2010). In order to alleviate pain, a drug must act on a target expressed at least in one of these structures
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