Table 1.
Drugs acting on GPCR targets on primary sensory neurons (PSNs) investigated in pre-clinical models of inflammatory and peripheral neuropathic pain (Evidence from 2018 to 2023)
| GPCR class | Receptor subtype | Expression/localization in different subtypes of PSNs in mouse and human DRG | Drug candidate | Route of administration | Animal model | Outcomes/mechanism of action |
|---|---|---|---|---|---|---|
| Opioid receptors | MOR | IHC [107]: Mouse: Peptidergic neuron (CGRP+) and myelinated neuron (NF200+). Sc-RNAseq: [36] Mouse:NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1), Cold (Trpm8). Human: NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1), Cold (Trpm8). |
DALDA (Agonist) (#) | Systemic (subcutaneous) | L5-SNL (rats) | Inhibits spontaneous and ongoing pain [21] |
| Systemic (subcutaneous) | Tibial SNI (mice) | • Inhibits mechanical and heat hypersensitivity • Inhibits high voltage activated calcium currents in DRG neurons [12] |
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| Systemic (subcutaneous) | CCI (rats) | • Inhibition of mechanical and thermal hypersensitivity [108] | ||||
| (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP) *Low Pka mediated pH dependent effect at injury site only |
Systemic (intravenous) | CCI (rats) | • Inhibition of mechanical and thermal hypersensitivity • Naloxone methiodide, a peripheral opioid antagonist, completely reversed the pain relief caused by NFEPP |
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| KOR | IHC [26]: Mouse: Peptidergic neuron (CGRP+) and myelinated neuron (NF200+) Sc-RNAseq: [36] Mouse: NP1 (Gfra1, Gfra2), NP2 (Gfra1), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1) Human: PEP1 (Adcyap1), PEP2 (Ntrk1) |
HSK21542 (Agonist) (#) | Systemic (intravenous) |
Paw incision; Sciatic CCI; (rats) |
• Inhibitions mechanical allodynia • Minimal central side effects in comparison to morphine [109] |
|
| SHR0687 (Agonist) (#) | Systemic (intravenous) | Carrageenan-induced pain | • Inhibits mechanical hypersensitivity [28] | |||
| FE200041 (Agonist) (#) | Systemic (Intravenous, subcutaneous) | Tail flick test Formalin test |
• Antinociceptive effect [28] | |||
| JT09 (Agonist) (#) | Systemic (oral) | Hot plate test Acetic acid induced writhing | • Antinociceptive effect | |||
| Opioid/neuropeptide FF receptors | Sc-RNAseq: [36] NPFFR1: Mouse: NP2 (Gfra1), PEP1 (Adcyap1), Cold (Trpm8) Human: PEP1 (Adcyap1), PEP2 (Ntrk1) NPFFR2: Mouse:NP1 (Gfra1, Gfra2), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1) Human: NP1 (Gfra1, Gfra2), PEP1 (Adcyap1), PEP2 (Fam19a1), Cold (Trpm8) |
Analogues of DN-9 (Agonist) (#) |
Systemic (oral) | Sciatic CCI; (mice) | • Inhibition of mechanical and thermal hypersensitivity • No tolerance, dependence, constipation, or respiratory depression at effective analgesic doses [75] |
|
| DOR/KOR | DOR: IHC [110]: Non peptidergic unmyelinated neuron (IB4+) and myelinated neuron (NF200+) Sc-RNAseq:[36] Mouse:NP1 (Gfra1, Gfra2), NP2 (Gfra1), PEP2 (Ntrk1) and PEP2 (Fam19a1) Human: NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1), Cold (Trpm8) |
CAV1001 (Agonist) (#) | Systemic (intraperitoneal) | L5-L6 SNL (rats) | • Inhibition of mechanical hypersensitivity [74] | |
| Cannabinoid receptors | CB1 | ISH [111]: Mouse: Non peptidergic unmyelinated neuron (IB4+), Peptidergic neuron (Trpv1+) and myelinated neuron (NF200+) Sc-RNAseq:[36] Mouse:NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1), Cold (Trpm8) Human: NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1), Cold (Trpm8) |
4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine or PRNMI (Agonist) (#) |
Systemic (intraperitoneal) Local (intraplantar) | CIPN (rats) | • Inhibition of mechanical and cold hypersensitivity • No tolerance and CNS associated side effects [112] |
| CB2 | RNAscope ISH [33]: Small and medium diameter sensory neurons after nerve injury. Single-cell-RNAseq: [36] Human: PEP2 (Fam19a1) |
AM1710 (Agonist) | Local (intraplantar) | CIPN (rats) | • Anti-allodynic effect [34] | |
| LY2828360 (Biased agonist) | Local (intraplantar) | Carrageenan | • Anti-allodynic effect [79] | |||
| CB1/CB2 | CB13 (Agonist) (#) | Systemic (oral) | Sciatic CCI (rats) | • Anti-allodynic effect [113] | ||
| Local (bath application) | CFA induced inflammatory pain (mice) | • Inhibits high voltage activated calcium currents in DRG neurons [30] | ||||
| Purinergic receptors | P2Y14R | IHC [114]: Mouse: Peptidergic neuron and myelinated neuron (NFH+) Single-cell-RNAseq: [36] Mouse:NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1), Cold (Trpm8) Human: NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1), Cold (Trpm8) |
4-[4-(4-Piperidinyl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxylic acid hydrochloride (Antagonist) |
Injection to trigeminal ganglion | CCI of the infraorbital nerve (mice) | • Inhibition of mechanical hypersensitivity [47] |
| Adenosine A1 receptor | IHC [115]: Mouse: Non peptidergic unmyelinated neuron (IB4+), Peptidergic neuron (CGRP+) and myelinated neuron (NF200+) Single-cell-RNAseq: [36] Mouse:NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1) Human: NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1) |
N6-cyclopentyladenosine (Agonist) | Local (Intraplantar) | Intraplantar glutamate injection (rats) | • Reduced spontaneous pain behavior [48] | |
| Adenosine A3 receptor | ICC [116]: Rat cultured DRG neurons Single-cell-RNAseq: [36] Human: NP3 (Sst), PEP2 (Ntrk1) *Debatable inter-species differences |
MRS5980 (Agonist) | Systemic (intraperitoneal) | Sciatic CCI (mice) | • PSNs A2 dependent anti-allodynia [51] | |
| Oxytocin receptor | IHC [117] Rat: Non peptidergic unmyelinated neuron (IB4+) and Peptidergic neuron (CGRP+) Single-cell-RNAseq: [36] Mouse: Cold (trpm8) Human: PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1) |
Oxytocin (agonist) | Injection to trigeminal ganglion | Alveolar nerve transection | • Inhibits mechanical hypersensitivity [55] | |
| Local (intraplantar) | SNL (rats) | • Inhibition of mechanical allodynia [118] | ||||
| Mrgpr | MrgprX1 | IHC [36]: Non peptidergic unmyelinated neuron (IB4+) and Peptidergic neuron (CGRP+) Single-cell-RNAseq: [36] Mouse:NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Fam19a1), Cold (Trpm8) Human [10]: NP1 (Gfra2) |
6-(tert-butyl)-5-(3,4-dichlorophenyl)-4-(2-(trifluoromethoxy)phenoxy)t hieno[2,3-d]pyrimidine (Positive allosteric modulator) | Systemic (Oral) | Sciatic CCI (MrgprX1 humanized mice) | • Attenuates heat hypersensitivity [38] |
| Chemokine receptors | CXCR5 | IHC [44]: Mouse: Non peptidergic unmyelinated neuron (IB4+), Peptidergic neuron (CGRP+) and myelinated neuron (NF200+) Single-cell-RNAseq: [36] Mouse: NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst) Human [10]:TRPA1+, PENK+, Cold, Aδ high-threshold nociceptors |
Cxcl13 siRNA | DRG microinjection | SNL (mice) | • Inhibition of mechanical and heat hypersensitivity [45] |
| CGRP receptor | Peptidergic neuron (CGRP+) Single-cell-RNAseq:[36] Mouse:NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1), Cold (trpm8) Human: NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1), Cold (trpm8) |
Olcegepant (Antagonist) | Temporo-mandibular joint injection | CFA injection in temporomandi bular joint (mice) | • Inhibition of Temporomandibular disorder associated pain [119] |
|
| Angiotensin II type 1 and 2 receptors | AT1Rs | IHC [120]: Rat: Non peptidergic unmyelinated neuron (IB4+) Single-cell-RNAseq: [36] Mouse:NP1 (Gfra1, Gfra2), NP2 (Gfra1), NP3 (Sst), PEP1 (Adcyap1), PEP2 (Ntrk1) and PEP2 (Fam19a1), Cold (trpm8) Human: NP1 (Gfra1, Gfra2), PEP1 (Adcyap1) |
Losartan (Antagonist) | Systemic (intraperitoneal) | CIPN | • Inhibition of cytokine release in DRG • Inhibits mechanical hypersensitivity [59] |
| AT2Rs | IHC: [120]: Rat: Non peptidergic unmyelinated neuron (IB4+) Single-cell-RNAseq: [36] Mouse: NP2 (Gfra1) |
EMA401 (Antagonist) | Systemic (Intraperitoneal, oral) | CIPN, sciatic CCI, SNI (rats and mice) | • Inhibits mechanical, heat and cold hypersensitivities [61] |
Abbreviations: NP, Non-peptidergic; PEP, peptidergic; IHC, Immunohistochemistry; ISH, In-situ hybridization; Sc-RNAseq, Single cell RNA sequencing; CGRP, Calcitonin gene-related peptide; IB4, isolectin B4; NF200, neurofilament-200; gfra1, GDNF Family Receptor Alpha 1; gfra2, GDNF Family Receptor Alpha 2; Sst, Somatostatin; Adcyap1, Adenylate Cyclase Activating Polypeptide 1; Ntrk1, neurotrophic tyrosine kinase receptor; Fam19a1, Family with sequence similarity 19 (chemokine (C-C motif)-like), member A1; Trpm8, Transient Receptor Potential Cation Channel Subfamily M Member 8.
The neuronal clustering approach is adopted from Jung et. al. 2023 [29].
Resources: https://sensoryomics.shinyapps.io/RNA-Data/
(#)
denotes peripherally restricted compounds