Author: Inturi, Nikhil Nageswar ; Tavares-Ferreira, Diana ; Kume, Moeno ; Mohammed, Ayaan ; Mwirigi, Juliet M ; Munro, Gordon ; Sankaranarayanan, Ishwarya ; Price, Theodore J ; Petersen, Kenneth A

Hyperalgesic priming is a model system that has been widely used to understand plasticity in painful stimulus-detecting sensory neurons, called nociceptors. A key feature of this model system is that following priming, stimuli that do not normally cause hyperalgesia now readily provoke this state. We hypothesized that hyperalgesic priming occurs due to reorganization of translation of mRNA in nociceptors. To test this hypothesis, we used paclitaxel treatment as the priming stimulus and translating ribosome affinity purification (TRAP) to measure persistent changes in mRNA translation in Nav1.8+ nociceptors. TRAP sequencing revealed 161 genes with persistently altered mRNA translation in the primed state. We identified Gpr88 as upregulated and Metrn as downregulated. We confirmed a functional role for these genes, wherein a GPR88 agonist causes pain only in primed mice and established hyperalgesic priming is reversed by Meteorin. Our work demonstrates that altered nociceptor translatomes are causative in producing hyperalgesic priming.

16 Jan 2019·ACS Chemical NeuroscienceQ3 · MEDICINE

Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target

Q3 · MEDICINE

Review

Author: Allen, John A. ; Zhou, Jia ; Tian, Sheng ; Li, Bang ; Ye, Na ; Mao, Qi ; Wold, Eric A.

Although G protein-coupled receptors (GPCRs) are recognized as pivotal drug targets involved in multiple physiological and pathological processes, the majority of GPCRs including orphan GPCRs (oGPCRs) are unexploited. GPR88, a brain-specific oGPCR with particularly robust expression in the striatum, regulates diverse brain and behavioral functions, including cognition, mood, movement control, and reward-based learning, and is thus emerging as a novel drug target for central nervous system disorders including schizophrenia, Parkinson's disease, anxiety, and addiction. Nevertheless, no effective GPR88 synthetic ligands have yet entered into clinical trials, and GPR88 endogenous ligands remain unknown. Despite the recent discovery and early stage study of several GPR88 agonists, such as 2-PCCA, RTI-13951-33, and phenylglycinol derivatives, further research into GPR88 pharmacology, medicinal chemistry, and chemical biology is urgently needed to yield structurally diversified GPR88-specific ligands. Drug-like pharmacological tool function and relevant signaling elucidation will also accelerate the evaluation of this receptor as a viable neurotherapeutic target.

100 Deals associated with GPR88 agonists(Acadia Pharmaceuticals)

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Preclinical	US	ACADIA Pharmaceuticals, Inc.	12 Jan 2024
Attention Deficit Disorder With Hyperactivity	Preclinical	US	ACADIA Pharmaceuticals, Inc.	12 Jan 2024
Bipolar and Related Disorders	Preclinical	US	ACADIA Pharmaceuticals, Inc.	12 Jan 2024
Drug abuse	Preclinical	US	ACADIA Pharmaceuticals, Inc.	12 Jan 2024
Huntington Disease-Like Syndrome	Preclinical	US	ACADIA Pharmaceuticals, Inc.	12 Jan 2024
Parkinson Disease	Preclinical	US	ACADIA Pharmaceuticals, Inc.	12 Jan 2024
Schizophrenia	Preclinical	US	ACADIA Pharmaceuticals, Inc.	12 Jan 2024
Tourette Syndrome	Preclinical	US	ACADIA Pharmaceuticals, Inc.	12 Jan 2024

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