Shedding Light on the Pharmacological Interactions between μ-Opioid Analgesics and Angiotensin Receptor Modulators: A New Option for Treating Chronic Pain

Abstract

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia.

Telmisartan Is a Promising Agent for Managing Neuropathic Pain and Delaying Opioid Analgesic Tolerance in Rats

“…The role of angiotensin receptors and ligands in the central nervous system (CNS) and their possible therapeutic use in the alleviation of NP, among other pain types, are emerging as an important area of pain research. Other groups and we ourselves have reported on the connection between the RAS and NP [5,21,22] and possible pharmacological interactions between the opioid and angiotensin systems regarding analgesia [23]. In the present work, we provide, to the best of our knowledge, the first evidence for enhanced analgesia following co-administration of a clinically, widely used, angiotensin receptor blocker (ARB) and morphine in a neuropathic rodent model.…”

“…Therefore, the need to develop novel drugs or new approaches encourages researchers to continue working in this field. In the last decades, many promising drug targets have been identified as potential therapeutic targets for future neuropathic pain treatment, such as angiotensin receptor type 1 [22,23]. The use of combination treatment regimens has also been considered in order to increase the effectiveness without increasing the undesirable effects of the elements of the combination.…”

The central renin angiotensin II system – a genetic pathway, functional decoding and selective target engagement characterization in humans

“…29 Accumulating evidence moreover suggests that central angiotensin inhibition modulates reward processing, reciprocal social interaction and pain processing via interactions with the opioid system. 30,31 The role of the AT1R in stimulating vasopressin 32 release may additionally mediate effects on anxiety during unpredictable threats 33 (for the anxiolytic potential of vasopressin in humans see Zhuang et al, 2021). 34 Together these studies describe further biological pathways that may mediate the complex effects of the AT1R, however, how these systems interact with the central AT1R system to regulate complex human behaviors has not been systematically examined.…”

Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery II

“…Three articles in this Special Issue explore dimerization and intracellular interactions and positive or negative cooperativity between the µOR and angiotensin (AT2) receptors [ 30 ], serotonin (5HT 1A ) receptor [ 31 ], and free fatty acid (FFA) receptors [ 32 ]. Kiraly et al reviewed positive cooperativity between µOR analgesics and angiotensin receptor inhibition [ 30 ].…”

“…Three articles in this Special Issue explore dimerization and intracellular interactions and positive or negative cooperativity between the µOR and angiotensin (AT2) receptors [ 30 ], serotonin (5HT 1A ) receptor [ 31 ], and free fatty acid (FFA) receptors [ 32 ]. Kiraly et al reviewed positive cooperativity between µOR analgesics and angiotensin receptor inhibition [ 30 ]. The premise of the review is based on studies, for example, that found angiotensin-converting enzyme inhibition enhancing morphine antinociception and reducing opioid antinociceptive tolerance [ 33 ] and that the activation of angiotensin AT2 receptor decreases morphine antinociception [ 34 ].…”