Peripherally acting opioid analgesics and peripherally-induced analgesia

Abstract

The management of pain, particularly chronic pain, is still an area of medical need. In this context, opioids remain a gold standard for the treatment of pain. However, significant side effects, mainly of central origin, limit their clinical use. Here, we review recent progress to improve the therapeutic and safety profiles of opioids for pain management. Characterization of peripheral opioid-mediated pain mechanisms have been a key component of this process. Several studies identified peripheral µ, δ, and κ opioid receptors (MOR, DOR, and KOR, respectively) and nociceptin/orphanin FQ (NOP) receptors as significant players of opioid-mediated antinociception, able to achieve clinically significant effects independently of any central action. Following this, particularly from a medicinal chemistry point of view, main efforts have been directed towards the peripheralization of opioid receptor agonists with the objective of optimizing receptor activity and minimizing central exposure and the associated undesired effects. These activities have allowed the characterization of a great variety of compounds and investigational drugs that show low central nervous system (CNS) penetration (and therefore a reduced side effect profile) yet maintaining the desired opioid-related peripheral antinociceptive activity. These include highly hydrophilic/amphiphilic and massive molecules unable to easily cross lipid membranes, substrates of glycoprotein P (a extrusion pump that avoids CNS penetration), nanocarriers that release the analgesic agent at the site of inflammation and pain, and pH-sensitive opioid agonists that selectively activate at those sites (and represent a new pharmacodynamic paradigm). Hopefully, patients with pain will benefit soon from the incorporation of these new entities.

An Hypothesis for CXCL1/CXCR2 Signaling Regulating Neutrophil-Derived Opioid Peptides Involved in Acupuncture for Inflammatory Pain

“…As the peripheral opioid peptides are without central side effects, the development of peripheral opioid agonists has attracted more attention. ere are kinds of peripheral opioid agonists in the current [20]. For peripheral endogenous opioid analgesia of inflammatory pain, little studies pay attention on how to increase the release of immune cell-derived opioids in the inflamed tissue.…”

“…Peripheral immune cell-derived opioid peptide analgesia has some advantages and characteristics as follows: (1) without detrimental side effects of central endogenous opioid, such as nausea, addiction, pain tolerance, and respiratory depression [3,19,20]; (2) it may have promising clinical application prospects in the treatment of chronic inflammatory pain. Studies have showed that, in early stages of inflammation (6 h after inflammation), both peripheral and central opioid receptors are involved in the antinociceptive effect [21], whereas in later stages (4-6 days after inflammation), endogenous analgesia is mediated exclusively by peripheral opioid and its receptors [19,22].…”

On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

“…There is substantial evidence demonstrating the involvement of peripheral ORs in MOR agonists-induced analgesia following systemic administration in acute thermal pain models in rat or mouse [34,42]. Research from our laboratory (Schmidhammer and Spetea's, Al-Khrasani and Fürst's and Benyhe's research teams) and others have reported on effective, peripheral analgesic effects of opioids following local or systemic administration applying various pharmacological approaches in rodent models of inflammatory and visceral pain [2,[35][36][37][38][39][43][44][45][46][47][48][49][50][51][52][53]. On the other hand, in animal models of neuropathic pain, the peripheral analgesic effect of opioids is a question of debate [54][55][56][57][58][59].…”

Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors

“…[42][43]58 KOR is well distributed throughout the CNS, as well as the PNS. 19 Furthermore, the presence of high levels of KOR in the nucleus accumbens shell and core, claustrum, ventral pallidum, medial habenula, caudate putamen, endoperiform nucleus, bed nucleus of the stria terminals, and amygdala was demonstrated by immunohistochemical and autoradiographic studies. [59][60] After the production of KOR in the ventral tegmental area, the receptors are transported to the nucleus accumbens and caudate putamen.…”

“…63 KOR is widely expressed in the PNS. 19,64 The need to cross the BBB is therefore avoided, alongside any possible CNS side effects. 19 KOR also seems to be involved in sedation and diuresis.…”