Sensory Neuron-Specific Deletion of Tropomyosin Receptor Kinase A (TrkA) in Mice Abolishes Osteoarthritis (OA) Pain via NGF/TrkA Intervention of Peripheral Sensitization

doi:10.3390/ijms232012076

. 2022 Oct 11;23(20):12076.

doi: 10.3390/ijms232012076.

Sensory Neuron-Specific Deletion of Tropomyosin Receptor Kinase A (TrkA) in Mice Abolishes Osteoarthritis (OA) Pain via NGF/TrkA Intervention of Peripheral Sensitization

InSug O-Sullivan¹, Ranjan Kc², Gurjit Singh¹, Vaskar Das³, Kaige Ma¹, Xin Li¹, Fackson Mwale⁴, Gina Votta-Velis^{5

6}, Benjamin Bruce⁶, Arivarasu Natarajan Anbazhagan⁷, Andre J van Wijnen⁸, Hee-Jeong Im^{1

6}

Affiliations

¹ Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA.
² Ocugen Inc., Malvern, PA 19355, USA.
³ Departments of Anesthesiology, Rush University, Chicago, IL 60612, USA.
⁴ Surgery, McGill University, Montreal, QC H3T 1E2, Canada.
⁵ Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, USA.
⁶ Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
⁷ Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
⁸ Biochemistry, University of Vermont, Burlington, VT 05405, USA.

PMID: 36292950
PMCID: PMC9602682
DOI: 10.3390/ijms232012076

Sensory Neuron-Specific Deletion of Tropomyosin Receptor Kinase A (TrkA) in Mice Abolishes Osteoarthritis (OA) Pain via NGF/TrkA Intervention of Peripheral Sensitization

InSug O-Sullivan et al. Int J Mol Sci. 2022.

. 2022 Oct 11;23(20):12076.

doi: 10.3390/ijms232012076.

Authors

Affiliations

¹ Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA.
² Ocugen Inc., Malvern, PA 19355, USA.
³ Departments of Anesthesiology, Rush University, Chicago, IL 60612, USA.
⁴ Surgery, McGill University, Montreal, QC H3T 1E2, Canada.
⁵ Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, USA.
⁶ Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
⁷ Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
⁸ Biochemistry, University of Vermont, Burlington, VT 05405, USA.

PMID: 36292950
PMCID: PMC9602682
DOI: 10.3390/ijms232012076

Abstract

Tropomyosin receptor kinase A (TrkA/NTRK1) is a high-affinity receptor for nerve growth factor (NGF), a potent pain mediator. NGF/TrkA signaling elevates synovial sensory neuronal distributions in the joints and causes osteoarthritis (OA) pain. We investigated the mechanisms of pain transmission as to whether peripheral sensory neurons are linked to the cellular plasticity in the dorsal root ganglia (DRG) and are critical for OA hyperalgesia. Sensory neuron-specific deletion of TrkA was achieved by tamoxifen injection in 4-week-old TrkA^fl/fl;Na_V1.8^CreERT2 (Ntrk1 ^fl/fl;Scn10a^CreERT2) mice. OA was induced by partial medial meniscectomy (PMM) in 12-week-old mice, and OA-pain-related behavior was analyzed for 12 weeks followed by comprehensive histopathological examinations. OA-associated joint pain was markedly improved without cartilage protection in sensory-neuron-specific conditional TrkA knock-out (cKO) mice. Alleviated hyperalgesia was associated with suppression of the NGF/TrkA pathway and reduced angiogenesis in fibroblast-like synovial cells. Elevated pain transmitters in the DRG of OA-induced mice were significantly diminished in sensory-neuron-specific TrkA cKO and global TrkA cKO mice. Spinal glial activity and brain-derived neurotropic factor (BDNF) were significantly increased in OA-induced mice but were substantially eliminated by sensory-neuron-specific deletion. Our results suggest that augmentation of NGF/TrkA signaling in the joint synovium and the peripheral sensory neurons facilitate pro-nociception and centralized pain sensitization.

Keywords: NGF/TrkA signaling; cellular plasticity; hyperalgesia; osteoarthritis; pain transportation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Global deletion of *TrkA* in mice relieved OA-associated hypersensitivity to pain and reduced expression of TrkA and NGF in the DRG but did not improve knee joint pathology with OA progression. (A) Development of mechanical allodynia (von Frey filament testing) in the ipsilateral hind paw, comparing *TrkA^fl/fl;Rosa^CreERT2*-negative (n = 11) and *TrkA^fl/fl;Rosa^CreERT2*-positive (n = 5) mice following PMM. (B) Histological assessment for proteoglycan depletion by Safranin-O fast green staining (×20). Each knee shown represents a group of mice (n = 4). (C) Severity of articular cartilage degradation was graded using the Osteoarthritis Research Society International (OARSI) scoring system. Values are mean ± SEM. Global deletion of *TrkA* in mice resulted in reduced expression of NGF. Immunofluorescence images of TrkA (D) and NGF (F) in the lumbar DRG (L3-L5) harvested at 12 weeks after PMM showed significant reduction of both TrkA and NGF in *TrkA^fl/fl;Rosa^CreERT2*-positive mice. The quantification of TrkA intensity (E) and NGF intensity (G) showed deletion of *TrkA* significantly reduced NGF in DRG (F,G). Values are mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns: not significant. p = 0.742 (sham), p = 0.582 (PMM). Scale bar: 100 μm.

**Figure 2**
Cartilage-specific deletion of *TrkA* in mice did not improve either OA-associated hypersensitivity to pain or knee joint pathology with OA progression. OA was induced by PMM in 12-week-old *TrkA^fl/fl;Aggrecan^CreERT2*-positive (n = 13) and *TrkA^fl/fl;Aggrecan^CreERT2*-negative control mice (n = 6), followed by harvesting knee joints at 12 weeks after PMM. Each knee shown is representative of a group of mice. (A) Development of mechanical allodynia (von Frey filament testing) in the ipsilateral hind paw, comparing *TrkA^fl/fl;Aggrecan^CreERT2*-negative and *TrkA^fl/fl;Aggrecan^CreERT2*-positive mice following PMM. There were no significant differences. (B) Ambulation (horizontal photo beam crossings) and (C) spontaneous rearing activity (vertical photo beam crossings) were not different in *TrkA*-deleted mice compared with the control after PMM, while both activities were reduced between pre- and advanced OA. (D) Histological assessment for proteoglycan depletion by Safranin-O fast green staining (×10). (E) Severity of articular cartilage degradation was graded using the Osteoarthritis Research Society International (OARSI) scoring system. Values are mean ± SEM. * p < 0.05, ns: not significant. p = 0.644 (sham), p = 0.376 (PMM).

**Figure 3**
NGF/TrkA supported OA pain transmission in the peripheral but not in the central nervous system. (A) Intrathecal (IT) injection of anti-NGF antibody in C57BL/6 mice at 13 weeks after PMM did not alleviate hyperalgesia from chronic osteoarthritis, indicating that pain transmission is not a central event but may occur through peripheral sensory neurons. OA was induced by partial medial meniscectomy (PMM) in 12-week-old wild-type C57Bl/6 mice (n = 7), followed by pain test with von Frey filament. At 13 weeks after PMM, 10 μg of anti-NGF antibody in 5 μL (2 μg/μL) was injected intrathecally, and pain was assessed at 1 h, 4 h, 8 h, and 24 h after IT injection. (B) Von Frey filament testing in the ipsilateral hindpaw of PKCδ null mice (n = 10) receiving intaarticular (IA) injection of anti-NGF-2.5S antibody (30 μg in 5 μL saline) twice a week until 8 weeks after DMM surgery. Mice injected with anti-NGF antibody showed significantly reduced pain from the third week of anti-NGF IA injection. Black arrows indicate the IA injection. Adapted from Kc et al., Figure 6H [11]. * p < 0.05, ** p < 0.01, ns: not significant. p = 0.35.

**Figure 4**
Sensory-neuron-specific deletion of *TrkA* in mice (*TrkA^fl/fl;Na_V1.8^CreERT2*-positive) abolished OA-associated hypersensitivity to pain as effectively as global deletion of *TrkA*, but did not improve knee joint pathology with OA progression. (A) Development of mechanical allodynia (von Frey filament testing) in the ipsilateral hind paw, comparing *TrkA^fl/fl;Na_V1.8^CreERT2*-negative (n = 9) and *TrkA^fl/fl;Na_V1.8^CreERT2*-positive (n = 12) mice following PMM. (B) Histological assessment for proteoglycan content by Safranin-O fast green staining (×20). Each knee shown is representative of a group of mice (n = 12, 9, 7, 8). (C) Severity of articular cartilage degradation was monitored by the OARSI scoring (n = 5). (D) Sensory-neuron-specific deletion of TrkA in mice (*TrkA^fl/fl;Na_V1.8^CreERT2*-positive) reduced NGF in DRG. Each image shown is representative of a group of mice (n = 5). Representative immunofluorescence staining for TrkA (green) in the DRG of *TrkA^fl/fl;Na_V1.8^CreERT2*-positive and Cre- control *TrkA^fl/fl;Na_V1.8^CreERT2*-negative mice. (E) Quantitative analysis of TrkA expression in the DRG. (F) Immunofluorescence staining for NGF (green) in DRG. (G) Quantitative analysis of NGF expression in DRG. All quantitative analysis values are mean ± SEM. ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns: not significant. p = 0.284 (sham), p = 0.12 (PMM), p = 0.327 (sham vs. *TrkA^fl/fl;Na_V1.8^CreERT2*-positive PMM). Scale bar: 100 μm.

**Figure 5**
Immunofluorescence staining of peripheral nerve fiber sprouting, angiogenesis factor, pro-inflammatory cytokines, and MMP-13 in osteoarthritis (OA) synovium correlated with decreased joint pain sensation in OA. Reduced PGP9.5 (A,B) expression in joint tissues indicated less synovial sensory fiber and downregulated neural fiber. (A) Representative immunofluorescence images of staining for PGP9.5 (green) in knee joint synovium of *TrkA^fl/fl;Na_V1.8^CreERT2*-negative (n = 9) and *TrkA^fl/fl;Na_V1.8^CreERT2*-positive (n = 12) mice. (B) Quantitative analyses of nerve fiber sprouting. The density of PGP9.5 fibers of *TrkA^fl/fl;Na_V1.8^CreERT2*-negative mice exhibited a significant increase in synovial/capsular regions compared to *TrkA^fl/fl;Na_V1.8^CreERT2*-positive mice. PGP9.5+ nerve fiber density was calculated as the intensity of the nerve fiber area. 4′,6-Diamidino-2-phenylindole (DAPI) stained nuclei blue. *** p < 0.001. (C–F) Reduced angiogenesis factor CD31 (C) and VEGF (E) and quantification of CD31 (D) and VEGF (F) expression in joint tissues indicated decreased innervation and angiogenesis markers. Significantly decreased expression of both CD31 and VEGF (green; (C,E)) in the knee joint synovium of *TrkA*-deleted mice after PMM compared to *TrkA^fl/fl;Na_V1.8^CreERT2*-negative control mice. Each group: n = 5. Quantitative analysis of CD31 (D) and VEGF (F) expression in the synovium. (G–L) Pro-inflammatory cytokines TNF-α, IL-1β, and cartilage-degrading enzyme MMP-13 correlated with the unprotected joint pathology. Representative immunofluorescence images of tumor necrosis factor-α (TNF-α) (green) expression in the synovium of *TrkA^fl/fl;Na_V1.8^CreERT2*-positive mice and *TrkA^fl/fl;Na_V1.8^CreERT2*-negative control mice are shown in (G). Each group: n = 5. Quantitative analyses of TNF-α expression in cartilage and synovium (H). (I) Representative immunofluorescence images of interleukin (IL)-1β expression (green) in cartilage and synovium of *TrkA^fl/fl;Na_V1.8^CreERT2*-positive mice and *TrkA^fl/fl;Na_V1.8^CreERT2*-negative control mice are shown. Each group: n = 5. (J) Quantitative analyses of IL-1β expression in cartilage and synovium. (K) Immunofluorescence images of MMP-13 expression in the synovium of *TrkA^fl/fl;Na_V1.8^CreERT2*-positive and *TrkA^fl/fl;Na_V1.8^CreERT2*-negative mice. Each group: n = 5. (L) Quantitative analyses of MMP-13 expression in synovium. Values are mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns: not significant. p = 0.418 (PGP 9.5 sham vs. *TrkA^fl/fl;Na_V1.8^CreERT2*-positive PMM), p = 0.230 (IL-1β sham vs. *TrkA^fl/fl;Na_V1.8^CreERT2*-positive PMM), p = 0.911 (MMP-13 *TrkA^fl/fl;Na_V1.8^CreERT2*-negative vs.-positive PMM). 4′,6-Diamidino-2-phenylindole (DAPI) stained nuclei blue. Scale bar: 50 μm.

**Figure 6**
Immunofluorescence staining of peripheral nerve fiber sprouting, angiogenesis factor, pro-inflammatory cytokines, and MMP-13 in osteoarthritis (OA) synovium correlated with decreased joint pain sensation in OA. Reduced PGP9.5 expression in joint tissues indicated less synovial sensory fiber and downregulated neural fiber. (A) Representative immunofluorescence images of staining for PGP9.5 (green) in knee joint synovium of *TrkA^fl/fl;Rosa^CreERT2*-negative (n = 11) and *TrkA^fl/fl;Rosa^CreERT2*-positive (n = 5) mice. (B) Quantitative analyses of nerve fiber sprouting. PGP9.5+ nerve fiber density was calculated as the intensity of the nerve fiber area. 4′,6-Diamidino-2-phenylindole (DAPI) stained nuclei blue. (C–F) Reduced angiogenesis factor CD31 (C) and VEGF (E) and quantification of CD31 (D) and VEGF (F) expression in joint tissues indicated decreased innervation and angiogenic markers in the knee joint synovium of *TrkA*-deleted mice after PMM compared to *TrkA^fl/fl;Rosa^CreERT2*-negative control mice. Quantitative analysis of CD31 (D) VEGF (F) expression in the synovium. Immunofluorescence staining of TNF-α (G) and interleukin (IL)-1β (I) expression of MMP-13 (K) in *TrkA^fl/fl;Rosa^CreERT2*-positive mice following PMM surgery. Representative immunofluorescence images of tumor necrosis factor-α (TNF-α) (green) expression in synovium of *TrkA^fl/fl;Rosa^CreERT2*-positive mice and *TrkA^fl/fl;Rosa^CreERT2*-negative control mice are shown in (G). Each group: n = 5. Quantitative analyses of TNF-α expression in the synovium (H). (I) Representative immunofluorescence images of interleukin (IL)-1β expression (green) in cartilage and synovium of *TrkA^fl/fl;Rosa^CreERT2*-positive mice and *TrkA^fl/fl;Rosa^CreERT2*-negative control mice are shown. Each group: n = 5. (J) Quantitative analyses of IL-1β expression in cartilage and synovium. (K) Immunofluorescence images of MMP-13 expression in the synovium of *TrkA^fl/fl;Rosa^CreERT2*-positive and *TrkA^fl/fl; Rosa^CreERT2*-negative mice. Each group: n = 5. (L) Quantitative analyses of MMP-13 expression in the synovium. Values are mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns: not significant. p = 0.867 (PGP 9.5 sham vs. *TrkA^fl/fl;Rosa^CreERT2*-positive PMM), p = 0.138 (CD31 sham vs. *TrkA^fl/fl;Rosa^CreERT2*-positive PMM), p = 0.390 (VEGF sham vs. *TrkA^fl/fl;Rosa^CreERT2*-positive PMM), p = 0.464 (TNF-α sham vs. *TrkA^fl/fl;Rosa^CreERT2*-positive PMM), p = 0.073 (IL-1β *TrkA^fl/flRosa^CreERT2*-negative vs. -positive PMM), p = 0.986 (MMP-13 *TrkA^fl/fl;Rosa^CreERT2*-negative vs. -positive PMM). 4′,6-Diamidino-2-phenylindole (DAPI) stained nuclei blue. Scale bar: 50 μm.

**Figure 7**
Sensory-neuron-specific deletion of *TrkA* in OA mice (*TrkA^fl/fl;Na_V1.8^CreERT2*-positive) and global deletion of *TrkA* in OA mice (*TrkA^fl/fl;Rosa^CreERT2*-positive) reduced pain molecules substance P and CGRP significantly in DRG. (A) Representative immunofluorescence staining for SP (green), NeuN (red), and 4′,6-diamidino-2-phenylindole (DAPI)-stained nuclei (blue) in the DRG of sham, *TrkA^fl/fl;Na_V1.8^CreERT2*-negative PMM mice, *TrkA^fl/fl;Na_V1.8^CreERT2*-positive PMM mice, *TrkA^fl/fl;Rosa^CreERT2*-negative OA mice, and *TrkA^fl/fl;Rosa^CreERT2*-positive OA mice. (B) Representative immunofluorescence staining for CGRP (green), NeuN (red), and 4′,6-diamidino-2-phenylindole (DAPI)-stained nuclei (blue) in the DRG of sham, *TrkA^fl/fl;Na_V1.8^CreERT2*-negative PMM mice, *TrkA^fl/fl;Na_V1.8^CreERT2*-positive PMM mice, *TrkA^fl/fl;Rosa^CreERT2*-negative PMM mice, and *TrkA^fl/fl;Rosa^CreERT2*-positive PMM mice. (C) Quantitative analysis of SP expression in the DRG. (D) Quantitative analysis of CGRP expression in the DRG. Values are mean ± SEM. ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns: not significant. p = 0.117 (SP sham vs. *TrkA^fl/fl;Rosa^CreERT2*-positive PMM), p = 0.06 (SP sham vs. *TrkA^fl/fl;Na_V1.8^CreERT2*-positive PMM), p = 0.08 (CGRP sham vs. *TrkA^fl/fl;Rosa^CreERT2*-positive PMM), p = 0.596 (CGRP *TrkA^fl/fl;Na_V1.8^CreERT2*-negative PMM vs. *TrkA^fl/fl;Rosa^CreERT2*-negative PMM). Scale bar: 100 μm.

**Figure 8**
Sensory-neuron-specific deletion of *TrkA* in mice (*TrkA^fl/fl;Na_V1.8^CreERT2*-positive) reduced glial cell activity and pain molecule CGRP and BDNF significantly in spinal cords. (A) Representative immunofluorescence images of staining for IBA-1 (green) in SC of *TrkA^fl/fl;Na_V1.8^CreERT2*-negative (n = 9), *TrkA^fl/fl;Na_V1.8^CreERT2*-positive (n = 12), *TrkA^fl/fl;Rosa^CreERT2*-negative (n = 11), and *TrkA^fl/fl;Rosa^CreERT2*-positive (n = 5) mice. (B) Quantitative analyses of IBA-1. Following PMM surgery, 4′,6-diamidino-2-phenylindole (DAPI) stained nuclei blue. (C,D) Astroglial marker GFAP expression (green; (C)) and quantification of GFAP (D) in the SC of *TrkA*-deleted mice after PMM compared to *TrkA^fl/fl;Na_V1.8^CreERT2*-negative (n = 9), *TrkA^fl/fl;Na_V1.8^CreERT2*-positive (n = 12), *TrkA^fl/fl;Rosa^CreERT2*-negative (n = 11), and *TrkA^fl/fl;Rosa^CreERT2*-positive (n = 5) mice. 4′,6-Diamidino-2-phenylindole (DAPI) stained nuclei blue. Not significant compared between sham control and *TrkA^fl/fl;Na_V1.8^CreERT2* +ve mice and *TrkA^fl/fl;Rosa^CreERT2*-positive with PMM. Representative immunofluorescence images of tumor necrosis factor-α (TNF-α) expression and quantitative analyses (E,F), interleukin (IL)-1β expression and quantitative analyses (G,H), CGRP expression and quantitative analyses (I,J), and BDNF expression and quantitative analyses (K,L) in SC of sham control, *TrkA^fl/fl;Na_V1.8^CreERT2*-negative, *TrkA^fl/fl;Na_V1.8^CreERT2* +ve, *TrkA^fl/fl;Rosa^CreERT2*-negative, and *TrkA^fl/fl;Rosa^CreERT2*-positive mice are shown. Values are mean ± SEM. 4′,6-Diamidino-2-phenylindole (DAPI) stained nuclei blue. * p < 0.05, ** p < 0.01 *** p < 0.001, **** p < 0.0001, ns: not significant. p = 0.962 (IBA-1 sham vs. *TrkA^fl/fl;Rosa^CreERT2*-positive PMM), p = 0.062 (TNF-α sham vs. *TrkA^fl/fl;Rosa^CreERT2*-negative PMM), p = 0.234 (IL-1β sham vs. *TrkA^fl/fl;Rosa^CreERT2*-positive PMM), p = 0.051 (IL-1β *TrkA^fl/fl;Na_V1.8^CreERT2*-negative PMM vs. *TrkA^fl/fl;Rosa^CreERT2*-negative PMM), p = 0.434 (CGRP sham vs. *TrkA^fl/fl;Rosa^CreERT2*-positive PMM), p = 0.809 (CGRP *TrkA^fl/fl;Na_V1.8^CreERT2*-negative PMM vs. *TrkA^fl/fl;Rosa^CreERT2*-negative PMM), p = 0.123 (BDNF sham vs. *TrkA^fl/fl Na_V1.8^CreERT2*-positive PMM), p = 0.663 (BDNF *TrkA^fl/fl;Na_V1.8^CreERT2* vs. *TrkA^fl/flRosa^CreERT2*-negative PMM). Scale bar: 50 μm.

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[1] Cieza A., Causey K., Kamenov K., Hanson S.W., Chatterji S., Vos T. Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:2006–2017. doi: 10.1016/S0140-6736(20)32340-0. - DOI - PMC - PubMed

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[3] Skúladóttir H., Sveinsdottir H., Holden J.E., Gunnarsdóttir T.J., Halldorsdottir S., Björnsdottir A. Pain, Sleep, and Health-Related Quality of Life after Multidisciplinary Intervention for Chronic Pain. Int. J. Environ. Res. Public Healt. 2021;18:10233. doi: 10.3390/ijerph181910233. - DOI - PMC - PubMed

[4] Skúladóttir H., Sveinsdottir H., Holden J.E., Gunnarsdóttir T.J., Halldorsdottir S., Björnsdottir A. Pain, Sleep, and Health-Related Quality of Life after Multidisciplinary Intervention for Chronic Pain. Int. J. Environ. Res. Public Healt. 2021;18:10233. doi: 10.3390/ijerph181910233. - DOI - PMC - PubMed

[5] Kloppenburg M., Berenbaum F. Osteoarthritis year in review 2019: Epidemiology and therapy. Osteoarthr. Cartil. 2020;28:242–248. doi: 10.1016/j.joca.2020.01.002. - DOI - PubMed

[6] Kloppenburg M., Berenbaum F. Osteoarthritis year in review 2019: Epidemiology and therapy. Osteoarthr. Cartil. 2020;28:242–248. doi: 10.1016/j.joca.2020.01.002. - DOI - PubMed

[7] Mills S.E., Nicolson K.P., Smith B.H. Chronic pain: A review of its epidemiology and associated factors in population-based studies. Br. J. Anaesth. 2019;123:e273–e283. doi: 10.1016/j.bja.2019.03.023. - DOI - PMC - PubMed

[8] Mills S.E., Nicolson K.P., Smith B.H. Chronic pain: A review of its epidemiology and associated factors in population-based studies. Br. J. Anaesth. 2019;123:e273–e283. doi: 10.1016/j.bja.2019.03.023. - DOI - PMC - PubMed

[9] Bouhassira D., Lantéri-Minet M., Attal N., Laurent B., Touboul C. Prevalence of chronic pain with neuropathic character-istics in the general population. Pain. 2008;136:380–387. doi: 10.1016/j.pain.2007.08.013. - DOI - PubMed

[10] Bouhassira D., Lantéri-Minet M., Attal N., Laurent B., Touboul C. Prevalence of chronic pain with neuropathic character-istics in the general population. Pain. 2008;136:380–387. doi: 10.1016/j.pain.2007.08.013. - DOI - PubMed

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Sensory Neuron-Specific Deletion of Tropomyosin Receptor Kinase A (TrkA) in Mice Abolishes Osteoarthritis (OA) Pain via NGF/TrkA Intervention of Peripheral Sensitization

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Sensory Neuron-Specific Deletion of Tropomyosin Receptor Kinase A (TrkA) in Mice Abolishes Osteoarthritis (OA) Pain via NGF/TrkA Intervention of Peripheral Sensitization

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Abstract

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