Table 2.
Summary of TRPV1 Antagonists in Chronic Pain Models.
| Reference | Model | Species | Compound (Dose; Route; Frequency; Duration) | Stimulus and Effects |
|---|---|---|---|---|
| [54] | CCI | rat | siRNA (1 μg; i.th.) | Decreased CCI-cold (acetone) hypersensitivity by 50% and blocked capsaicin-induced behaviors. |
| [34] | SNL | rat | AS ODN (45 μg b.i.d.; i.th.) | Partially reversed SNL tactile (e-von Frey) hypersensitivity. |
| [34] | SNL | rat | thioxo-BCTC (2.15–21.5 mg/kg; i.v.) | Reduced tactile (e-vonFrey) hypersensitivity by ~70% at high dose (ED50 value of 10.6 mg/kg). |
| [53] | SNL | mouse | TRPV1 shRNAtg | TRPV1 shRNAtg mice did not develop tactile (e-von Frey or von Frey) hypersensitivity and had significantly decreased latencies on the 48 ºC and 58 ºC hotplate. |
| [63] | MIA | Rat | A-889425 (10–300 μmol/kg; p.o.); (10–30 μmol/kg; i.v.) | A-889425 completely reversed MIA-induced impaired grip strength and attenuated evoked and spontaneous firing by 44% and 61%, respectively, compared to baseline. |
| [61] | MIA | rat | A-784168 (3–30 μmol/kg; p.o.); (10–100 nmol; i.th.)
A-795614 (30–300 μmol/kg; p.o.); (10–100 nmol; i.th.) |
A-784168 significantly reversed MIA-induced weight bearing differences with an ED50 value of 8 μmol/kg, p.o and 22 nmol, i.th. A-795614 significantly reversed MIA-induced weight bearing differences with an ED50 value of 280 μmol/kg, p.o. and 26 nmol, i.th. |
| [47] | BCP | mouse | JNJ-17203212 (30 mg/kg; s.c.; b.i.d for 8–12 d) | TRPV1 KO and JNJ-17203212 attenuated spontaneous (~50%) and palpation-induced (~50%) flinching. JNJ-17203212 attenuated palpitation-induced increases in spinal lamina I-II c-Fos expression (7.5 cFos-IR) compared to vehicle (17.5 cFos-IR). |
| [64] | SCD | mouse | A-425619 (100 μM/kg; i.p.) | A-425619 significantly attenuated tactile (von Frey) hypersensitivity (30–90 min) in mice expressing human sickle hemoglobin in erythroid cells compared to vehicle treated mice. Electrophysiology ex vivo skin preparations from mice had C- and high threshold Aδ-fiber sensitization to mechanical force that was attenuated by A-425619. |
| [57] | MIA CCI SNL | ratmouse | A-425619 (30–300 μmol/kg; i.p.) | A-425619 reversed MIA weight-bearing to 47% of normal weight distribution and reversed von Frey tactile hypersensitive 2 weeks after SNL (36% reversal) or CCI (36% reversal) surgery. |
| [60] | MIABCP | ratmouse | ABT-102 (3–100 μmol/kg, p.o.; single dose or
b.i.d. for 12 d) A-993610 (μmol/kg, p.o. single dose or b.i.d. for 12 d) |
Acutely, ABT-102 significantly reversed MIA-induced difference in weight bearing (ED50 = 30 μmol/kg) and grip strength (ED50 = 10 μmol/kg). ABT-102 significantly reversed CBP-induced spontaneous guarding by 85%, decreased ambulation by 85% and palpation induced pain by 65%.
Doses of ABT-102 that had minimal effects acutely were more effective following chronic administration and significantly reversed MIA-induced decreased grip strength, bone cancer decreased spontaneous ambulation, ongoing pain and palpation evoked pain. Similar improvements in pain behaviors were observed after acute and chronic A-993610. Effects were not due to drug accumulation. |
| [58] | SNL | rat | A-425619 (3–30 mg/kg; i.p.)
A-840257 (3–30 mg/kg; i.p.) |
A-425619 and A-840257 lacked effects on von Frey tactile hypersensitivity in the SNL model of neuropathic pain. |
| [36] | CCI | rat | BCTC (30–300 nmol; p.o.) | 100 and 300 nmol BCTC produced a modest, though significant reversal of CCI-induced tactile (von Frey) hypersensitivity 30 min (but not 60 or 120 min) after administration. |
| [62] | CFA | A-889425 (10–100 μmol; i.p.) | A-889425 significantly attenuated CFA-induced tactile hypersensitivity at 30 and 100 μmol. Electrophysiology recordings from WDR neurons had significantly greater spontaneous and evoked firing, which was attenuated by A-889425 administration. | |
| [48] | BCP | mouse | I-RTX (0.03–1 μmol; i.p.) | I-RTX significantly decreased spontaneous flinching, attenuated decreased ambulation and reversed weight-bearing differences during ambulation in sarcoma-treated mice. |
| [56] | PSNL | rat | BCTC (1–30 mg/kg; p.o.) | BCTC partial attenuated PSNL von Frey tactile hypersensitivity (~50%) with significant reversal at 10 and 30 mg/kg. |
| [38] | MIA | rat | A-995662 (3–100 μmol/kg; p.o.; single dose or b.i.d. for 12 d) | Acute doses of A-995662 significantly reversed MIA-induced decreased grip strength. An acutely sub-effective (22% reversal) dose significantly restored grip force (91% reversal) after chronic administration. The duration of effectiveness was longer than the detection of compound in brain or plasma. |
| [35] | SNL | mouse | A-425619 (200 μmol/kg; i.p.) | A-425619 completely attenuated SNL-induced radiant heat thermal hypersensitivity. |
| [55] | CFA, PSNL | guinea pig, rat, mouse | capsazepine (10–100 mg/kg; s.c.) | Rodent species were insensitive to capsazepine reversal of hypersensitivity in inflammatory and neuropathic models. In guinea pigs, capsazepine produced an 80% reversal of PSNL-induced mechanical hypersensitivity. |
AS ODN, antisense oligonucleotides; BCP, bone cancer pain; CFA, Complete Freund’s Adjuvant; CCI, chronic constriction injury; b.i.d.; twice daily; d, day; e-von Frey, electronic von Frey; IR, immunoreactivity; i.p., intraperitoneal; i.th., intrathecal; KO, knock-out; MIA, mono iodoacetate; PSNL, partial sciatic nerve ligation; p.o., per os; SCD, sickle cell disease; siRNA, small interfering RNA; shRNAtg, small hairpin RNA transgenic; SNL, spinal nerve ligation; s.c., subcutaneous; WDR, wide dynamic range.