VGLUTs and Glutamate Synthesis—Focus on DRG Neurons and Pain
Abstract
:1. Vesicular Glutamate Transporters in Primary Afferent Neurons
- (1)
- Terminology (IASP)
- Hyperalgesia: Increased pain from a stimulus that normally provokes pain.
- Allodynia: Pain due to a stimulus that does not normally provoke pain.
- Neuropathic pain: Pain caused by a lesion or disease of the somatosensory nervous system.
- Nociceptive pain: Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors.
- (2)
- Pain-Like Behavior Tests
- (A)
- Thermal pain threshold *
- a)
- Tail withdrawal (heat sensitivity) test [3]: The distal half of the tail is dipped into a thermostatically controlled warm-hot water bath.
- b)
- Hot plate test [3]: Animal is placed on a warmed metal plate.
- c)
- Hargreaves test [3]: The plantar surface of the hindpaws is exposed to radiant heat, producing a continuous but discrete rise in temperature.
- d)
- Acetone test [3]: The plantar surface of the hindpaws is exposed to a droplet of acetone.
- e)
- Cold ethanol test [4]: The distal half of the tail is immersed in −14 °C to −15 °C ethanol.
- f)
- Dry ice pellet test [5]: The plantar surface of the hindpaws is exposed to a dry ice pellet 1 cm in diameter.
- (B)
- Mechanical pain threshold * [3]
- a)
- Randall-Sellito test: The plantar or dorsal surfaces of the hindpaws are exposed to increasing mechanical force (tip of the device). The maximum force applied is limited to 250 g to avoid skin damage.
- b)
- Von Frey test: The plantar surface of the hindpaw is exposed to a series of nylon monofilaments of different thicknesses, exerting varying degrees of pressure. The lesser monofilament inducing hindpaw withdrawal is recorded.
- (C)
- Itch
- a)
- Spontaneous itch behavior [6]: Itch behavior is recorded for 30 min using a digital video camera. One bout of scratching by either hindpaw is defined as a scratching episode and quantified.
Target | DRG level | Vglut1 | Vglut2 | Vglut3 | |||
---|---|---|---|---|---|---|---|
Protein | Transcript | Protein | Transcript | Protein | Transcript | ||
Hindpaw | L4-5 | ∼37% [32] | ∼40% [13] | ∼65% [9] | ∼70% [13] | ∼10% [30] | ∼17% [13] |
∼12% [9] | ∼90% [25] | ∼80% [25] | ∼19% [33] | ∼16% [33] | |||
Colorectum | T8-L1 | ∼15% [8] | — | ∼98% [8] | — | ∼17% [29] | — |
L6-S2 | ∼8% [8] | — | ∼97% [8] | — | ∼4% [29] | — | |
Urinary bladder | T8-L1 | ∼39% [7] | — | ∼94% [7] | — | ∼28% [7] | — |
L6-S2 | ∼26% [7] | — | ∼94% [7] | — | ∼8% [7] | — |
2. Role of VGLUTs in Pain Mechanisms—Lessons from Transgenic Mice
2.1. Global Deletion of VGLUTs
- (1)
- Inflammatory Pain Models [42] +
- a)
- Nerve growth factor (NGF)
- b)
- Capsaicin
- c)
- Formalin
- d)
- Carrageenan
- e)
- CFA (complete Freund´s adjuvant)
- (2)
- Neuropathic Pain Models [1] *
- a)
- Spared nerve injury (SNI): Tibial and common peroneal nerves (two of the three branches of the sciatic nerve) are axotomized (completely sectioned), while the sural nerve is left intact.
- b)
- Chronic constriction injury (CCI): Three to four light ligatures are placed around the sciatic nerve at the mid thigh level.
- c)
- Partial sciatic nerve injury (PSNL): A tight ligation of the dorsal third to half of the common sciatic nerve at the upper-thigh level is produced.
- d)
- Incisional pain: Skin of the plantar surface of the hindpaw is cut using a sharp blade, followed by suturing.
- e)
- Oxaliplatin (antineoplastic drug)-induced pain: Oxaliplatin is administered systemically #.
2.1.1. Global Deletion of VGLUTs and Effect on Nociceptive or Inflammatory Pain
Nociceptive Pain | Itch | ||||||
---|---|---|---|---|---|---|---|
Thermal | Mechanical | Visceral | |||||
Tail Withdrawal | Hot Plate | Hargreaves | Acetone, Cold ethanol, Dry ice pellet | Randall-Sellito | Von Frey | ||
Global KO | |||||||
VG1 (+/−) [40] | VG1 (+/−) [40] | — | — | — | VG1 (+/−) [40] | VG1 (+/−) [40] | — |
VG2 (+/−) [40,41] | VG2 (+/−) [40,41] | VG2 (+/−) [40,41] | — | — | VG2 (+/−) [40] | VG2 (+/−) [40] | — |
— | VG3 (−/−) [30,31] | VG3 (−/−) [30] | VG3 (−/−) [30,31] | VG3 (−/−) [30] | VG3 (−/−) [30,31] | VG3 (−/−) # | — |
Targeted KO | |||||||
VG2-DRG [26] | — | VG2-DRG [26] | — | VG2-DRG [26] | VG2-DRG [26] | — | VG2-DRG [26] |
VG2-nocicept. [25] | VG2-nocicept. [25] | VG2-nocicept. [25] | VG2-nocicept. [25] | VG2-nocicept. [25] | VG2-nocicept. [25] | — | VG2-nocicept. [25] |
— | — | VG2-TRPV1 [6,28,38] | VG2-TRPV1 * [38] | VG2-TRPV1 [6] | VG2-TRPV1 [6,28,38] | — | VG2-TRPV1 [6,28,38] |
— | VG2- TH [6] | VG2 –TH [6] | — | VG2 –TH [6] | VG2 –TH [6] | — | VG2-TH [6] |
— | VG2-Nav1.8 [27] | VG2-Nav1.8 [6,27] | VG2-Nav1.8 [27] | VG2-Nav1.8 [27] | VG2- Nav1.8 [27] | — | VG2-Nav1.8 [6,27] |
— | — | VG3-DRG [33] | — | VG3-DRG [33] | VG3- DRG [33] | — | — |
Inflammatory Pain | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
NGF | Capsaicin | Formalin | Carrageenan | CFA | ||||||
Mech. | Heat | Mech. | Licking Biting | Phase I | Phase II | Mech. | Heat | Cold | Mech. | Heat |
Global KO | ||||||||||
— | — | — | — | VG1 (+/−) [40] | VG1 (+/−) [40] | — | VG1 (+/−) [40] | — | — | — |
— | — | — | — | VG2 (+/−) [40,41] | VG2 (+/−) [40,41] | — | VG2 (+/−) [40,41] | — | — | — |
— | — | VG3 (−/−) [30] | — | VG3 (−/−) [30] | VG3 (−/−) [30] | VG3 (−/−) [30,31] | VG3 (−/−) & [30,31] | VG3 (−/−) [31] | — | — |
Targeted KO | ||||||||||
VG2-DRG [26] | VG2-DRG [26] | — | — | VG2-DRG [26] | VG2-DRG [26] | VG2-DRG [26] | VG2-DRG [26] | — | — | — |
— | — | — | VG2-nocicept. [25] | VG2-nocicept. [25] | VG2-nocicept. [25] | VG2-nocicept. [25] | VG2-nocicept. [25] | — | VG2-nocicept. [25] | VG2-nocicept. [25] |
VG2-TRPV1 δ [28] | VG2-TRPV1 + [28] | — | — | VG2-TRPV1 £ [6,28,38] | VG2-TRPV1 + [6,28,38] | VG2-TRPV1 + [28] | VG2-TRPV1 + [28] | — | — | — |
— | — | — | — | VG2-TH [6] | VG2-TH [6] | — | — | — | — | — |
— | VG2- Nav1.8 [27] | — | — | VG2- Nav1.8* [27] | VG2- Nav1.8 * [27] | — | — | — | — | — |
— | — | — | VG3-DRG [33] | — | — | VG3-DRG [33] | VG3-DRG [33] | — | VG3-DRG [33] | VG3-DRG [33] |
Neuropathic Pain | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
SNI | CCI | PSNL | Incisional | Oxaliplatin | ||||||||
Mech. | Cold | Mech. | Hargr. | Cold | Mech. | Hargr. | Cold | Mech. | Hargr. | Mech. | Hargr. | Cold |
Global KO | ||||||||||||
VG1 (+/−) [40] | VG1 (+/−) [40] | VG1 (+/−) [40] | — | VG1 (+/−) [40] | — | — | — | — | — | — | — | — |
VG2 (+/−) [40,41] | VG2 (+/−) [40,41] | VG2 (+/−) [40] | — | VG2 (+/−) [40] | — | — | — | — | — | — | — | — |
VG3 (−/−) [30] | — | VG3 (−/−) [31] | VG3 (−/−) [31] | VG3 (−/−) [31] | — | — | — | VG3 (−/−) [30] | VG3 (−/−) [30] | VG3 (−/−) [31] | VG3 (−/−) [31] | VG3 (−/−) [31] |
Targeted KO | ||||||||||||
— | — | — | — | — | VG2-DRG [26] | VG2-DRG [26] | VG2-DRG [26] | — | — | — | — | — |
— | — | VG2-nocicept. [25] | VG2-nocicept. [25] | — | — | — | — | — | — | — | — | — |
— | — | — | — | — | VG2-TRPV1 [43] | VG2-TRPV1 [43] | VG2-TRPV1 [43] | — | — | — | — | — |
— | — | — | — | — | VG2-Nav1.8 [27] | VG2-Nav1.8 [27] | VG2-Nav1.8 [27] | — | — | — | — | — |
VG3-DRG [33] | — | — | — | — | — | — | — | — | — | — | — | — |
2.1.2. Global Deletion of VGLUTs and Effect on Neuropathic Pain
2.2. Conditional Deletion of VGLUTs
2.2.1. VGLUT2-DRG-KO Mice
2.2.2. VGLUT2-Nociceptors-KO Mice
2.2.3. VGLUT2-TRPV1-KO Mice
2.2.4. VGLUT2-TH-KO or NaV1.8-KO Mice
2.2.5. VGLUT3-DRG-KO Mice
2.3. VGLUT Deletion, Visceral Pain and Itch
3. Mechanisms Associated with VGLUT Deletion and Pain Modulation
4. Glutamate Biosynthesis and VGLUT Interactions—Possible Implications to Pain
5. Conclusions
Acknowledgments
Conflicts of Interest
References
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Malet, M.; Brumovsky, P.R. VGLUTs and Glutamate Synthesis—Focus on DRG Neurons and Pain. Biomolecules 2015, 5, 3416-3437. https://doi.org/10.3390/biom5043416
Malet M, Brumovsky PR. VGLUTs and Glutamate Synthesis—Focus on DRG Neurons and Pain. Biomolecules. 2015; 5(4):3416-3437. https://doi.org/10.3390/biom5043416
Chicago/Turabian StyleMalet, Mariana, and Pablo R. Brumovsky. 2015. "VGLUTs and Glutamate Synthesis—Focus on DRG Neurons and Pain" Biomolecules 5, no. 4: 3416-3437. https://doi.org/10.3390/biom5043416