Side Effects of Opioids Are Ameliorated by Regulating TRPV1 Receptors.

Xiaqing Wang,Zhenjiang Li,Lupeng Yue,Chongyu Bao,Li Hu

doi:10.3390/ijerph19042387

Abstract

Humans have used opioids to suppress moderate to severe pain for thousands of years. However, the long-term use of opioids has several adverse effects, such as opioid tolerance, opioid-induced hyperalgesia, and addiction. In addition, the low efficiency of opioids in controlling neuropathic pain limits their clinical applications. Combining nonopioid analgesics with opioids to target multiple sites along the nociceptive pathway may alleviate the side effects of opioids. This study reviews the feasibility of reducing opioid side effects by regulating the transient receptor potential vanilloid 1 (TRPV1) receptors and summarizes the possible underlying mechanisms. Blocking and activating TRPV1 receptors can improve the therapeutic profile of opioids in different manners. TRPV1 and μ-opioid receptors are bidirectionally regulated by β-arrestin2. Thus, drug combinations or developing dual-acting drugs simultaneously targeting μ-opioid and TRPV1 receptors may mitigate opioid tolerance and opioid-induced hyperalgesia. In addition, TRPV1 receptors, especially expressed in the dorsal striatum and nucleus accumbens, participate in mediating opioid reward, and its regulation can reduce the risk of opioid-induced addiction. Finally, co-administration of TRPV1 antagonists and opioids in the primary action sites of the periphery can significantly relieve neuropathic pain. In general, the regulation of TRPV1 may potentially ameliorate the side effects of opioids and enhance their analgesic efficacy in neuropathic pain.

Highlights

Humans have used opioids for thousands of years to suppress pain or gain euphoria.At present, opioids are still the mainstay of acute pain management, but their long-term use has severe side effects, including opioid tolerance, opioid-induced hyperalgesia, dependence, and addiction [1]
Rowan et al demonstrated that chronic activation of peripheral μ-opioid receptors with prototypical μ-opioid receptor selective agonists (DAMGO and morphine) leads to the recruitment of β-arrestin2 to μopioid receptors and away from transient receptor potential vanilloid 1 (TRPV1), simultaneously causing the sensitization of TRPV1 in primary sensory neurons and contributing to behavioral symptoms of opioid-induced hyperalgesia [32]
Nguyen et al demonstrated that repeated morphine treatment increases μ-opioid receptor binding and the expression of adenylyl cyclase 1 (AC1), p38 mitogen-activated protein kinase (p38 MAPK), and nucleus factor kappa B (NF-κB) in the dorsal striatum (DSt); by contrast, these phenomena are suppressed by the TRPV1 antagonist capsazepine

Summary

Introduction

Humans have used opioids for thousands of years to suppress pain or gain euphoria. At present, opioids are still the mainstay of acute pain management, but their long-term use has severe side effects, including opioid tolerance, opioid-induced hyperalgesia, dependence, and addiction [1]. TRPV1, a transient receptor potential ion channel family member, is a molecular detector for physical stimuli. TRPV1 expression in the spinal cord, DRG, and sciatic nerve [29,30], whereas blockade of TRPV1 with its antagonist SB366791 potentiates the analgesic effects of systemic morphine in mice with bone cancer [31]. Another TRPV1 antagonist, capsazepine, can strengthen morphine antinociception in mice [32]. We summarize the role of TRPV1 in antinociception and its potential to reduce the side effects of opioids, such as opioid tolerance, opioid-induced hyperalgesia, addiction, and inefficiency in the mitigation of neuropathic pain. Our review may provide researchers with a concise and clear perspective to weigh the value and potency of TRPV1 as an auxiliary target in pain relief

Opioid Tolerance and Opioid-Induced Hyperalgesia

Addiction

In Neuropathic Pain

Discussion

Conclusions