Table 3 Summary of all included studies.
Author (Year) | Animal used | Number of animals | Injury model | Level of injury | Cannabinoid receptor agonists used | Cannabinoid receptor antagonists or inverse agonists used | Dose escalation study? | Outcomes assessed | Time of assessment | Key findings |
|---|---|---|---|---|---|---|---|---|---|---|
Genovese et al. (2008) [43] | CD1 mice | 30 | Traumatic SCI Compression of spinal cord for 1 min using aneurysm clip (24 g) | T5-T8 | • PEA | • None | • No | • BBB score | • Once a day for 10 days after SCI. | • PEA pre- or post-treatment reduced functional deficits (p < 0.05). |
Kwiatkoski et al. (2012) [39] | Wistar rats | 28 | Cryogenic SCI Liquid nitrogen jet applied to spinal cord for 5 s | T10 | • CBD | • None | • No | • BBB Score | • Before surgery and day 1, 3 and 7 after surgery | • CBD treatment improved locomotor function (p < 0.05). |
Su et al. (2017) [41] | Sprague-Dawley rats | 50 | Traumatic SCI 10 g impactor dropped from 25 mm. | T9–10 | • WIN | • AM 251 • AM 630 | • No | • BBB Score | • Day 1, 3, 7, 14, 21 and 28 after SCI. | • WIN improved BBB scores (p < 0.01). • AM 630, but not AM251, abrogated the BBB score improvement by WIN (p < 0.01). |
Impellizzeri et al. (2017) [45] | CD1 mice | 80 | Traumatic SCI Compression of spinal cord for 1 min using microaneurysm clip (24 g) | T6–7 | • PEA-OXA | • None | • No | • Basso Mouse Scale | • Daily for 10 days after SCI. | • PEA-OXA reduced functional deficits induced by SCI (p < 0.05). • No significant difference between intraperitoneal or oral administration of PEA-OXA. |
Paterniti et al. (2013a) [47] | PPAR-αKO mice (homozygous for the Pparatm1Gonz targeted mutation, strain name: 129S4/SvJae-Pparatm1Gonz/J) and litter-mate | 390 | Traumatic SCI Compression of spinal cord for 1 min using microaneurysm clip (24 g) | T6–7 | • PEA | • GW9662 • GSK0660 | • No | • Basso Mouse Scale | • Daily for 10 days after SCI. | • PEA improved BMS scores (p < 0.05). • GSK0660 and GW9662 abolished the effect of PEA • Genetic absence of the PPAR-α receptor in PPAR-αKO mice blocked the effect of the PEA. |
Paterniti et al. (2013b) [48] | CD1 mice | 50 | Traumatic SCI Compression of spinal cord for 1 min using microaneurysm clip (24 g) | T6–7 | • PEA • PEA + Luteolin • Co-ultramicronized composite of PEA and Luteolin (co-ultraPEALut) | • None | • No | • Basso Mouse Scale | • Daily for 10 days after SCI. | • PEA, luteolin or a combination of PEA and luteolin had no effect on functional deficits. • Co-ultraPEALut reduced locomotor deficits (p < 0.01). |
Latini et al. (2014) [40] | Wistar rats | 40 | Traumatic SCI Lateral cervical spinal cord hemisection (SCH) using iridectomy scissors. | C4 | • JWH-015 | • SR2 | • No | • Beam-walking test • catWalk | • Beam walking: Day 0 (control), 1, 3, 5, 7, 21 and 60 days after surgery. • catWalk: Day 7, 21, 60 | • JWH-015, but not SR2, improved locomotor function as assessed by beam walking and catWalk (p < 0.001). |
Jing et al. (2017) [38] | Sprague-Dawley rats | 168 | Ischemia/Reperfusion Injury Cross-clamp applied to aortic arch (between left common carotid artery and left subclavian artery) for 14 min. | N/A | • None | • AM 251 • AM 630 | • No | • Tarlov scoring system | • 4 h and 24 h after reperfusion. | • AM 251 and AM 630 both abolished the neuroprotective effects of remote ischaemic preconditioning prior to SCI (p < 0.05). |
Huo et al. (2018) [37] | Sprague-Dawley rats | 40 | Spinal cord ischaemia Catheter occlusion (catheter tip was at the level of the subclavian artery of aorta) for 12 min. | N/A | • WIN | • AM 251 • AM 630 | • No | • 14-point motor deficit index (MDI) score | • 48 h after reperfusion | • WIN improved MDI scores compared to control group (Control 5 [2], WIN 55,212-2 2.5[1.25]; p < 0.05). • AM 630, but not AM 251 reduced the effect of WIN on MDI scores (WIN 55,212-2 2.5[1.25], AM 630 5.2[1.25]; p < 0.01). • (Data expressed as median [interquartile range]) |
Su et al. (2009) [42] | Sprague-Dawley rats | 64 | Ischemia/Reperfusion Injury Aortic occlusion with Fogarthy catheter (catheter tip was at level of left subclavian artery) for 12 min | N/A | • None | • AM 251 • AM 630 | • No | • 14-point motor deficit index (MDI) score | • 24 and 48 h after reperfusion. | • AM 251, but not AM 630, abrogated the protective effects of remote ischaemic preconditioning prior to SCI (p < 0.05). |
Hong et al. (2015) [44] | C57BL/6J mice | 53 (one mouse in the vehicle group died so only 52 survived the full 21 day experimental period. | Traumatic SCI 1.5 mm silicon tube placed into the T11 vertebral canal for 60 min | T11 | • ACEA | • None | • No | • Rodent rotarod • Basso Mouse scale • Spontaneous open field locomotor activity • Elevated plus maze test (looking at anxiolytic effects | • Rodent rotarod: 1 day prior to and 1, 2, 7, 14, and 21 days after injury. • Basso Mouse scale for locomotion: 21 days after injury. • Spontaneous open field locomotor activity: 1, 2, 4, 24 h post treatment. • Elevated plus maze test: after 2 weeks of treatment. | • ACEA improved rotarod function (p = 0.04) and BMS scores (ACEA = 8 ± 3, vehicle = 5 ± 6; p = 0.02). • ACEA did not affect spontaneous activity or anxiolysis. |
Arevalo-Martin et al. (2012) [31] | CD1 mice | 35 | Traumatic SCI Contusive injury using 200Kdyn for 5 seconds | T8 | • None | • AM 281 • AM 630 | • No | • BBB Score • Hind paw withdrawal from hot and cold plates. • von Frey filament test | • BBB Score: day 7, 14, 30, 60, 90 post SCI. • Hind paw withdrawal to a noxious thermal stimulus: tested twice with a 30 min interval, on day 60 and 90 post SCI. | • BBB Locomotor Scale: AM 281 and AM 630 reduced recovery in motor function (p < 0.05) • Hind paw withdrawal to noxious thermal stimulus: AM 281 and AM 630 had no notable effect. • Von Frey Filament test: AM 281 and AM 630 had no notable effect. |
Li et al. (2018) [46] | C57BL/6 mice | 25 | Traumatic SCI Contusive injury by impactor drop from 3mm to deliver 60 kdyn force to spinal cord. | T9–10 | • CBD | • None | • No | • Basso Mouse Scale • Hindpaw withdrawal from thermal stimulus • von Frey filaments test | • Basso Mouse Scale: Day 1, 3, 7 and thereafter once weekly for 10 weeks • Hindpaw withdrawal from thermal stimulus: before surgery then week 4, 6, and 10 after SCI. • Von Frey filaments test: before surgery then week 2, 4, 6, 8, 10 after SCI. | • CBD had no effect on locomotor function assessed using the Basso Mouse Scale. • CBD reduced thermal (p < 0.0001) and mechanical (p = 0.04) hypersensitivity. |
Ahmed et al. (2010) [30] | Sprague-Dawley rats | 91–99 (unclear) | Traumatic SCI Contusive spinal cord injury using 10 g rod dropped from height of 12.5 mm | T9 | • WIN | • AM 251 • AM 630 | • Yes | • Hind paw withdrawal to noxious thermal stimulus | • Pre-SCI. • Day 21, 28, 35, 42 post SCI, 45 min after drug administration. | • WIN 55,212-2 produced dose-dependent reduction in thermal hyperalgesia (p < 0.05). • Effect abolished by antagonist AM 630 but not AM 251. |
Hama et al. (2007) [32] | Sprague-Dawley rats | 48 | Traumatic SCI Compression of spinal cord for 1 min using microaneurysm clip (24 g) | T6-T8 | • WIN | • AM 251 • AM 630 | • Yes | • von Frey filament test | • Baseline taken after SCI. • Agonist Experiment: Once every 30 min for 120 min following injection. • Agonist + Antagonist Experiment: 30 min after injection of agonist and antagonist | • WIN produced dose-dependent reduction withdrawal thresholds (WIN 55,212-2 0.2 mg/kg increased hindpaw withdrawal latency from 9.5 ± 0.4 s to 11.1 ± 0.5 s on day 42 post injury; p < 0.05. WIN 55,212-2 2 mg/kg increased hindpaw withdrawal latency from 8.4 ± 0.4 s to 10.7 ± 0.4 s on day 42 post injury; p < 0.0001) • Effect blocked by AM 251 but not AM 630 (withdrawal threshold after AM 630 pre-treatment = 9.9 ± 0.6 s, after WIN 55–212,2 post-treatment = 8.6 ± 1.0 s; p > 0.05. After-AM 251 pre-treatment 9.7 ± 0.6 s, after WIN 55–212,2 post-treatment 12.0 ± 0.7 s; p < 0.0001) |
Hama et al. (2009) [33] | Sprague-Dawley rats | 23 | Traumatic SCI Compression of spinal cord for 1 min using microaneurysm clip (20 g) | T6–7 | • WIN | • None | • Yes | • von Frey filament test | • Baseline taken before SCI, then before and 30 min after each injection of WIN for 7 days | • WIN produced dose-dependent reduction withdrawal thresholds (p < 0.05) • Effect was maintained throughout the 7 day experimental period. |
Hama et al. (2010) [34] | Sprague-Dawley rats | n = 452–488 (Unclear) | Traumatic SCI Compression of spinal cord for 1 min using microaneurysm clip (20 g) | T6–7 | • Acetaminophen (APAP) • Gabapentin • Memantine hydrochloride • Memantine sulphate • Morphine • Tramadol | • AM 251 • AM 630 • Naloxone | • Yes | • von Frey filament test | • Baseline taken 4 weeks after spinal cord compression. • Experiment 1: Every 30 min up to 120 min post-injection. • Experiment 2: 60 or 90 min after the second injection depending on the particular combination. | • APAP + Gabapentin combination demonstrated synergy (p < 0.05). Reduction in withdrawal thresholds was attenuated by AM 251 but not AM 630 (p < 0.05). • APAP + Memantine combination was merely additive. • APAP + Morphine combination demonstrated synergy (p < 0.05). Reduction in withdrawal thresholds was attenuated by AM 251 and AM 630 (p < 0.05). • APAP + Tramadol combination was merely additive. Reduction in withdrawal thresholds was attenuated by AM 251 and naloxone but not AM 630 (p < 0.05). • AM 251, AM 630 and naloxone did not affect withdrawal thresholds when given alone or prior to individual drugs. |
Hama et al. (2011) [35] | Sprague-Dawley rats | 198–206 (unclear) | Traumatic SCI Compression of spinal cord for 1 min using microaneurysm clip (20 g) | T6–7 | • WIN | • Hemopressin • Rimonabant | • Yes | • von Frey filament test | • Single drug experiment: Prior to drug administration and every 30 min up to 2 h post injection. • Drug combination experiment: Prior to, and 30 min after WIN treatment. | • Intrathecal WIN 57.4 nmol increased withdrawal thresholds (p < 0.05). Lower doses had no effect. • Intracerebroventricular WIN produced a dose-dependent increase in withdrawal thresholds (p < 0.05). • Rimonabant and hemopressin did not alter withdrawal thresholds when used singly. • Rimonabant, but not hemopressin, blocked the antinociceptive effects of WIN (p < 0.05). |
Hama et al. (2014) [36] | Sprague-Dawley rats | 120 | Traumatic SCI Compression of spinal cord for 1 min using microaneurysm clip (20 g) | T6–7 | • CP 55,940 | • Rimonabant • SR 144538 | • Yes | • von Frey filament test | • Experiment 1 (Acute dose of CP 55,940): Before injection, every 30 min up to 120 min post injection. • Experiment 2 (Repeat drug treatment): After 8 am injection for 7 days. • Experiment 3 (Antagonist pre-treatment before CP 55,940 administration): Before pre-treatment and 30 and 60 min after treatment. | • Experiment 1: CP 55,940 produced dose-dependent increase in withdrawal thresholds (p < 0.05). • Experiment 2: Antinociceptive effects of CP 55,940 was maintained at full efficacy throughout 7 day experimental period. • Experiment 3: Pre-treatment with rimonabant, but not SR 144528 blocked the effect of CP 55,940 (p < 0.05). |
