Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings
Abstract
:1. Introduction
2. Signaling Mechanism of Pain
3. Epigenetic Pathway of Pain
4. Mediators and Molecular Targets of Pain—An Overview
5. Classical Pain Models—An Overview
5.1. Inflammatory Pain Models
5.1.1. Complete Freund’s Adjuvant (CFA) Induced Inflammatory Pain Model
5.1.2. Formalin-Induced Nociceptive Pain Model
5.2. Visceral Pain Mechanisms Through Animal Models
The Colorectal Distension (CRD) Model
5.3. Mechanisms and Models of Neuropathic Pain
5.3.1. The Chronic Constriction Injury (CCI)
5.3.2. Spinal Nerve Ligation Model
5.3.3. Chronic Constriction of the Infraorbital Nerve Model
5.3.4. The Chronic Compression of Dorsal Root Ganglion (CCD) Model
5.3.5. STZ-Induced Diabetic Neuropathic Pain Model
5.3.6. Burn Injury-Induced Pain
5.4. Cancer Pain Mechanisms Through Animal Models
5.4.1. Syngeneic Tumor Implantation Model of Pain
5.4.2. Bone Metastasis Model of Pain
5.4.3. Development of Colorectal Carcinoma Metastasis Model of Pain
5.5. Genetically Modified Pain Models
5.5.1. TRPV1 Knockout Mice
5.5.2. OPRM1 Knockout Mice
5.5.3. TRPV1 Overexpression Mice
5.5.4. Nav1.7 Knock-In Mice
5.5.5. P2X3 Knockout Mice
5.5.6. Application of CRISPR in Pain Research: A Promising Frontier
5.5.7. CRISPR on Identification of Novel Pain Targets and Elucidating Pain Pathways
5.6. Cellular Models of Pain
5.6.1. Reprogrammed Nociceptor Neurons from Fibroblasts
5.6.2. Human-Induced Pluripotent Stem Cells (HiPSCs)
5.6.3. Human and Rat hDRG Neuronal Cultures for Pain Drug Discovery
5.7. Alternative to Animal Models of Pain
5.7.1. Zebrafish (Danio rerio)—A Fish Model
5.7.2. Drosophila melanogaster: A Fruit Fly Model
5.7.3. Caenorhabditis elegans: A Nematode Model
5.8. Human Experimental Models of Pain
5.8.1. The Heat/Capsaicin Sensitization Model
5.8.2. Intradermal Capsaicin Model
5.8.3. The Cold Pressor Model
5.8.4. The Ultraviolet Light UV-B Pain Model
5.9. Role Human Volunteers in Advancing Pain Research and Ethical Considerations
5.10. Neuroimaging Techniques in Pain Research
5.10.1. Functional Magnetic Resonance Imaging (fMRI)
5.10.2. Positron Emission Tomography (PET)
5.10.3. Neuroimaging on Brain Circuitry, Plasticity and Pain Modulation
5.11. Microbiome in Pain Research
5.12. Computational and Mathematical Models in Pain Research
6. Animal Models of Pain: A Critical Evaluation of Validity
7. Progress and Challenges in Translational Pain Research
8. Pain Models and Analgesic Drug Discovery
Novel Pain Drug Development Using Animal Models
9. Review Summary
- Key areas of focus include:
- Molecular pain research: This includes investigating pain at the molecular level using techniques like genomics and proteomics, including employing gene editing, omics, and imaging to enhance pain research. It also includes utilizing high-resolution imaging to study pain pathways in real-time and at a cellular resolution, as well as studying the role of ion channel modulation in pain neurons for potential therapeutic targets.
- Genetically Modified Models: Advances in genetic engineering have led to the development of transgenic and knockout mice, allowing researchers to study the role of specific genes in pain pathways.
- In vitro models: These involve utilizing human sensory neurons (such as HiPSCs) and stem cell-derived nerves for preclinical research.
- Behavioral Assessments: These allow for improved methods for assessing pain-related behaviours in animals, including non-reflexive and voluntary behaviors, to better capture the complexity of pain.
- Bridging the gap: This entails addressing the disparity between animal and human pain through refined methods and measures, including developing models that reflect the genetic and phenotypic diversity of human populations, to better understand individual differences in pain perception and treatment responses
- Multimodal Approaches: These entail combining different types of pain models (e.g., inflammatory, neuropathic) to study the interplay between various pain mechanisms, as well as combining animal models with genomics, proteomics, and metabolomics to identify novel pain biomarkers and therapeutic targets.
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Pain Models | Applications | Limitations | Possible Underlying Mechanisms and Pathways | |
---|---|---|---|---|
Inflammatory Pain | Complete Freund’s Adjuvant (CFA) |
| Variability in response based on species difference |
|
Formalin tests |
| It may not fully replicate all types of clinical pain conditions. |
| |
Visceral Pain | Colorectal Distension (CRD) |
| Invasiveness |
|
Neuropathic Pain | The Chronic Constriction Injury (CCI) |
| Technically challenge, may not fully replicate all aspects of human neuropathic pain. Variability in response Invasiveness |
|
Spinal Nerve Ligation Model | Neuropathic pain research and Drug screening | Model complexity Species differences |
| |
Chronic Constriction of the Infraorbital Nerve Model |
| Variability in response | STAT3 pathways in astrocytes via IL6 TRPV channels | |
The Chronic Compression of Dorsal Root Ganglion (CCD) | Drug Development and Neuropathic Pain Research | Variability in response | CXCL12/CXCR4 Signaling | |
STZ-induced DNP model | To study mechanisms of painful diabetic neuropathy and to evaluate potential therapies | Various differences in how the model works and how real diabetes happens compared to human diabetes | Increased expression of Nav1.3, Nav1.6, and Nav1.9 channels in DRG neurons | |
Cancer Pain |
|
|
|
|
Genetically Modified |
|
|
|
|
Cellular Models |
|
| Cell viability (The cells may not fully replicate the in vivo environment. | Voltage-Gated Sodium Channels (Nav) |
Compound Name | Target/Class of Drug | The Type of Pain Studied | The Type of Animal Model Used |
---|---|---|---|
EMA401 (Olodanrigan) | Selective AT2R receptor antagonist | Neuropathic Pain | Chronic constriction injury |
GR79236 IB-MECA (Piclidenoson) | A1R agonist A3R agonist | Neuropathic Pain | Neuropathic pain models |
Pn3a | Nav1.7 antagonist | Nociception Neuropathic Pain Inflammatory pain | Hotplate, formalin, carrageenan, CFA |
BAY-390 | TRPA1 Agonist | Neuropathic Pain | Cinnamaldehyde |
HC-030031 | TRPA1 Agonist | Neuropathic pain Inflammatory pain | UV-light B-induced burn injury model (Sun-burn thermal injury) |
GRCI7536 | TRPA1 Agonist | Diabetic neuropathic pain | Neuropathic pain model |
Resiniferatoxin (RTX) | TRPV1 Agonist | Neuropathic pain | L5 Nerve Injury model |
CBD3063 | Cav2.2 antagonist | Neuopathic pan Inflammatory pain | The spinal nerve injury model, Hot plate, cold plate tests, Chronic constriction injury |
EST73502 (Bifunctional ligand) | MOR (µ) agonist Sigma (σ) Receptor antagonist | Neuropathic Pain Cancer Pain Arthritic pain | Partial sciatic nerve ligation Paw Pressure test |
Sulforaphane | MOR agonist | Neuropathic Pain | Chronic constriction injury Chronic constriction injury |
SB366791 PN6047 | VR1/TRPV1 antagonist MOR agonist | Neuropathic Pain Cancer Pain Inflammatory pain Acute dental Pain | The spinal nerve ligation; L5 Nerve injury model Rat model of Periodontal, mono-iodoacetate–-induced osteoarthritic pain model and carrageenan-induced acute inflammatory model |
ST171 | 5HT1AR agonist | Neuropathic pain (Acute and Chronic Pain) | Hot plate, Tail flick, CFA, Spinal Nerve injury models |
PG-110 (Antibody) | Anti-NGF | Inflammatory pain | CFA, L5 spinal nerve axotomy (SNA) model |
Tanezumab (Antibody) | Anti-Nrf2 | Neuropathic pain | Diabetic neuropathic models |
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Asiri, Y.I.; Moni, S.S.; Ramar, M.; Chidambaram, K. Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings. Pharmaceuticals 2024, 17, 1439. https://doi.org/10.3390/ph17111439
Asiri YI, Moni SS, Ramar M, Chidambaram K. Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings. Pharmaceuticals. 2024; 17(11):1439. https://doi.org/10.3390/ph17111439
Chicago/Turabian StyleAsiri, Yahya I., Sivakumar S. Moni, Mohankumar Ramar, and Kumarappan Chidambaram. 2024. "Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings" Pharmaceuticals 17, no. 11: 1439. https://doi.org/10.3390/ph17111439
APA StyleAsiri, Y. I., Moni, S. S., Ramar, M., & Chidambaram, K. (2024). Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings. Pharmaceuticals, 17(11), 1439. https://doi.org/10.3390/ph17111439