Multi-chemokine receptor antagonist RAP-103 inhibits opioid-derived respiratory depression, reduces opioid reinforcement and physical dependence, and normalizes opioid-induced dysregulation of mesolimbic chemokine receptors in rats

Bongiovanni, Angela R.; Zhao, Pingwei; Inan, Saadet; Wiah, Sonita; Shekarabi, Aryan; Farkas, Daniel; Watson, Mia N.; Wimmer, Mathieu E.; Ruff, Michael R.

doi:10.1016/j.drugalcdep.2022.109556

Cited by 7 publications

(4 citation statements)

References 89 publications

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“…Moreover, RAP-103 administered together with morphine enhances its analgesic effect in the DPN model, which is related to the fact that it increases the sensitivity of MOR and reduces the levels of the pronociceptive cytokines TNFα and CCL3, and it also slightly reduced CCL2 [340]. Importantly, in 2022, Bongiovanni et al reported that RAP-103 diminishes opioid-derived respiratory depression and physical dependence in rats [354]. The authors proposed that this multitarget chemokine receptor antagonist may lessen the risk of opioid abuse [354], which indicates that polytherapy may be useful for the management of both pain and opioid addiction.…”

Section: Analgesic Potential Of Targeting Multiple Chemokine Receptorsmentioning

confidence: 97%

“…Another interesting pharmacological tool is RAP-103, which blocks four chemokine receptors, CCR2, CCR5, CCR8 [353], and CXCR4, as the latest research shows [354]. It was already shown that RAP-103 prevents and/or diminishes established neuropathic pain hypersensitivity in rats after partial sciatic nerve injury [341] and in a diabetic peripheral neuropathy model [340].…”

Section: Analgesic Potential Of Targeting Multiple Chemokine Receptorsmentioning

confidence: 99%

“…Importantly, in 2022, Bongiovanni et al reported that RAP-103 diminishes opioid-derived respiratory depression and physical dependence in rats [354]. The authors proposed that this multitarget chemokine receptor antagonist may lessen the risk of opioid abuse [354], which indicates that polytherapy may be useful for the management of both pain and opioid addiction. Therefore, in light of the current literature, it can be said with certainty that by blocking several chemokine receptors that are significantly involved in nociceptive transmission, pain can be relieved; such therapeutic approaches may be extremely helpful in wide range of clinical applications, including opioid pharmacotherapy.…”

Section: Analgesic Potential Of Targeting Multiple Chemokine Receptorsmentioning

confidence: 99%

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Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

Pawlik

Mika

2023

Molecules

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Neuropathic pain is a debilitating condition that affects millions of people worldwide. Numerous studies indicate that this type of pain is a chronic condition with a complex mechanism that tends to worsen over time, leading to a significant deterioration in patients’ quality of life and issues like depression, disability, and disturbed sleep. Presently used analgesics are not effective enough in neuropathy treatment and may cause many side effects due to the high doses needed. In recent years, many researchers have pointed to the important role of chemokines not only in the development and maintenance of neuropathy but also in the effectiveness of analgesic drugs. Currently, approximately 50 chemokines are known to act through 20 different seven-transmembrane G-protein-coupled receptors located on the surface of neuronal, glial, and immune cells. Data from recent years clearly indicate that more chemokines than initially thought (CCL1/2/3/5/7/8/9/11, CXCL3/9/10/12/13/14/17; XCL1, CX3CL1) have pronociceptive properties; therefore, blocking their action by using neutralizing antibodies, inhibiting their synthesis, or blocking their receptors brings neuropathic pain relief. Several of them (CCL1/2/3/7/9/XCL1) have been shown to be able to reduce opioid drug effectiveness in neuropathy, and neutralizing antibodies against them can restore morphine and/or buprenorphine analgesia. The latest research provides irrefutable evidence that chemokine receptors are promising targets for pharmacotherapy; chemokine receptor antagonists can relieve pain of different etiologies, and most of them are able to enhance opioid analgesia, for example, the blockade of CCR1 (J113863), CCR2 (RS504393), CCR3 (SB328437), CCR4 (C021), CCR5 (maraviroc/AZD5672/TAK-220), CXCR2 (NVPCXCR220/SB225002), CXCR3 (NBI-74330/AMG487), CXCR4 (AMD3100/AMD3465), and XCR1 (vMIP-II). Recent research has shown that multitarget antagonists of chemokine receptors, such as CCR2/5 (cenicriviroc), CXCR1/2 (reparixin), and CCR2/CCR5/CCR8 (RAP-103), are also very effective painkillers. A multidirectional strategy based on the modulation of neuronal–glial–immune interactions by changing the activity of the chemokine family can significantly improve the quality of life of patients suffering from neuropathic pain. However, members of the chemokine family are still underestimated pharmacological targets for pain treatment. In this article, we review the literature and provide new insights into the role of chemokines and their receptors in neuropathic pain.

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Section: Analgesic Potential Of Targeting Multiple Chemokine Receptorsmentioning

confidence: 97%

Section: Analgesic Potential Of Targeting Multiple Chemokine Receptorsmentioning

confidence: 99%

Section: Analgesic Potential Of Targeting Multiple Chemokine Receptorsmentioning

confidence: 99%

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Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

Pawlik

Mika

2023

Molecules

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“…PhagoptosisRAP-103 is a popular orally available and stabilized pentapeptide analog of D-ala-peptide T-amide (DAPTA), an HIV gp120-derived chemokine (C-C motif) receptor 5 (CCR5) entry inhibitor 146. RAP-103 acts as a multi-chemokine receptor antagonist with a capacity in hindering the binding of chemokine ligands with four specific chemokine receptors: CCR2/5/8 as well as C-X-C chemokine receptor 4 (CXCR4) 147. Oral administration of RAP-103 hinders mechanical allodynia as well as suppresses thermal hyperalgesia under damaged sciatic nerve 148.…”

mentioning

confidence: 99%

Stress/cell death pathways, neuroinflammation, and neuropathic pain

Li,

et al. 2023

Immunological Reviews

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SummaryNeuropathic pain is a common and debilitating modality of chronic pain induced by a lesion or disease of the somatosensory nervous system. Albeit the elucidation of numerous pathophysiological mechanisms and the development of potential treatment compounds, safe and reliable therapies of neuropathic pain remain poor. Multiple stress/cell death pathways have been shown to be implicated in neuroinflammation during neuropathic pain. Here, we summarize the current knowledge of stress/cell death pathways and present an overview of the roles and molecular mechanisms of stress/cell death pathways in neuroinflammation during neuropathic pain, covering intrinsic and extrinsic apoptosis, autophagy, mitophagy, ferroptosis, pyroptosis, necroptosis, and phagoptosis. Small molecule compounds that modulate stress/cell death pathways in alleviating neuropathic pain are discussed mainly based on preclinical neuropathic pain models. These findings will contribute to in‐depth understanding of the pathological processes during neuropathic pain as well as bridge the gap between basic and translational research to uncover new neuroprotective interventions.

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The Inflammation/NF-κB and BDNF/TrkB/CREB Pathways in the Cerebellum Are Implicated in the Changes in Spatial Working Memory After Both Morphine Dependence and Withdrawal in Rat

Ahmadi,

Majidi,

Koraei

et al. 2024

Mol Neurobiol

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Multi-chemokine receptor antagonist RAP-103 inhibits opioid-derived respiratory depression, reduces opioid reinforcement and physical dependence, and normalizes opioid-induced dysregulation of mesolimbic chemokine receptors in rats

Cited by 7 publications

References 89 publications

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

Stress/cell death pathways, neuroinflammation, and neuropathic pain

The Inflammation/NF-κB and BDNF/TrkB/CREB Pathways in the Cerebellum Are Implicated in the Changes in Spatial Working Memory After Both Morphine Dependence and Withdrawal in Rat

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