Targeting sensory neuron GPCRs for peripheral neuropathic pain

Ankit Uniyal; Vinod Tiwari; Takashi Tsukamoto; Xinzhong Dong; Yun Guan; Srinivasa N Raja

doi:10.1016/j.tips.2023.10.003

Targeting sensory neuron GPCRs for peripheral neuropathic pain

Trends Pharmacol Sci. 2023 Dec;44(12):1009-1027. doi: 10.1016/j.tips.2023.10.003. Epub 2023 Nov 11.

Authors

Ankit Uniyal¹, Vinod Tiwari², Takashi Tsukamoto³, Xinzhong Dong⁴, Yun Guan⁵, Srinivasa N Raja⁶

Affiliations

¹ Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA.
² Neuroscience and Pain Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (B.H.U), Varanasi, India.
³ Department of Neurology and Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Neuroscience, The Johns Hopkins University, Baltimore, MD, USA.
⁵ Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA; Department of Neurological Surgery, The Johns Hopkins University, Baltimore, MD, USA.
⁶ Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, MD, USA; Department of Neurology and Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: sraja2@jhmi.edu.

Abstract

Despite the high prevalence of peripheral neuropathic pain (NP) conditions and significant progress in understanding its underlying mechanisms, the management of peripheral NP remains inadequate. Existing pharmacotherapies for NP act primarily on the central nervous system (CNS) and are often associated with CNS-related adverse effects, limiting their clinical effectiveness. Mounting preclinical evidence indicates that reducing the heightened activity in primary sensory neurons by targeting G-protein-coupled receptors (GPCRs), without activating these receptors in the CNS, relieves pain without central adverse effects. In this review, we focus on recent advancements in GPCR-mediated peripheral pain relief and discuss strategies to advance the development of more effective and safer therapies for peripheral NP by shifting from traditional CNS modulatory approaches toward selective targeting of GPCRs on primary sensory neurons.

Keywords: G-protein-coupled receptors; drug discovery; neuropathic pain; peripheral nervous system; primary sensory neurons; spontaneous discharge.

Publication types

Review

MeSH terms

Central Nervous System
Humans
Neuralgia* / drug therapy
Receptors, G-Protein-Coupled
Sensory Receptor Cells

Substances

Receptors, G-Protein-Coupled

Abstract

Publication types

MeSH terms

Substances

Grants and funding