Cannabis sativa L. Extract Alleviates Neuropathic Pain and Modulates CB1 and CB2 Receptor Expression in Rat
Abstract
:1. Introduction
2. Methods
2.1. Cannabis sativa L. (CSL) Extract Preparation
2.2. Characteristics of the CSL Extracts
Component | CBD-A | CBD | Δ9-THC-A | Δ9-THC |
Concentration [mg/g] | 1.2 | 215.2 | 0.15 | 13.3 |
Component | CBD-A | CBD | Δ9-THC-A | Δ9-THC |
Concentration [mg/g] | 1.2 | 220.2 | 0.1 | 15.5 |
2.3. Cannabinoid Identification and Quantification
2.4. Animal Study
2.4.1. Induction of Neuropathic Pain
2.4.2. Tail-Flick Test
2.4.3. The von Frey Test
2.5. Real-Time PCR
2.6. CNRI and CNR2 ELISA
2.7. Statistical Analysis
3. Results
3.1. Neuropathic Pain Induction and Treatment
3.2. The Influence of Neuropathic Pain Induction and Treatment on CB1R and CB2R Protein and mRNA Expression
3.2.1. Vincristine and Gabapentin Treatment on CB1R and CB2R Expression
3.2.2. CB1R Expression in the Rat Brain and Blood Lymphocytes
3.3. CB2R Expression in the Rat Brain and Blood Lymphocytes
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
CBD | Cannabidiol |
CBD-A | Cannabinoid acid |
CB1R | Cannabinoid receptor 1 |
CNRI | Cannabinoid receptor 1 gene |
CB2R | Cannabinoid receptor 2 |
CNR2 | Cannabinoid receptor 2gene |
RT-PCR | Real-Time PCR reaction |
Δ9-THC | THC-Δ9-Tetrahydrocannabinol, Tetrahydrocannabinol |
Δ9-THC-A | Δ9-Tetrahydrocannabinoid acid |
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Group | Intervention | Number of Rats |
---|---|---|
1 | NaCl (0.9%, 1 mL i.p.) + Rape oil (1 mL p.o.) | 10 |
2 | VK + Rape oil—1 mL p.o. | 10 |
3 | VK + Gabapentin (solution 1 mg/mL)—60 mg/kg bw p.o. | 10 |
4 | VK + Extract D—5.0 mg/kg bw p.o | 10 |
5 | VK + Extract D—7.5 mg/kg bw p.o | 10 |
6 | VK + Extract D—10.0 mg/kg bw p.o | 10 |
7 | VK + Extract D—20.0 mg/kg bw p.o | 10 |
8 | VK + Extract D—40.0 mg/kg bw p.o | 10 |
9 | VK + Extract B—5.0 mg/kg bw p.o | 10 |
10 | VK + Extract B—7.5 mg/kg bw p.o | 10 |
11 | VK + Extract B—10.0 mg/kg bw p.o | 10 |
12 | VK + Extract B—20.0 mg/kg bw p.o | 10 |
13 | VK + Extract B—40.0 mg/kg bw p.o | 10 |
Gene | Sequence 5′→ 3′ |
---|---|
CB1R | Primer F: TAATATGAAGCAAGATACCAG Primer R: CCATTTACAGAGACAACAAG |
CB2R | Primer F: CAGTTACAGAGACAGAGGC Primer R: TGTTTCCATTACCCTAGAGC |
GADPH | Primer F: GATGGTGAAGGTCGGTGTG Primer R: ATGAAGGGGTCGTTGATGG |
Group | t = 0 | t = 1 h | t = 2 h | t = 3 h | t = 6 h |
---|---|---|---|---|---|
Tail flick test | |||||
[s] | |||||
NaCl | 12.9 ± 0.7 | 12.2 ± 1.1 | 12.6 ± 0.9 | 12.7 ± 0.9 | 13.2 ± 1.1 |
VK | 9.7 ± 0.7 * | 10.1 ± 0.6 * | 9.5 ± 0.6 * | 9.8 ± 0.7 * | 9.7 ± 0.7 * |
Von Frey test | |||||
[g] | |||||
NaCl | 30.2 ± 0.6 | 30.6 ± 1.2 | 29.6 ± 0.9 | 28.9 ± 0.9 | 29.5 ± 0.4 |
VK | 27.4 ± 0.8 * | 27.2 ± 0.7 * | 27.4 ± 0.7 * | 27 ± 0.7 * | 26.6 ± 0.5 * |
Group | t = 0 | t = 1 h | t = 2 h | t = 3 h | t = 6 h |
---|---|---|---|---|---|
Tail flick test | |||||
[s] | |||||
VK | 9.7 ± 0.7 | 10.1 ± 0.6 | 9.5 ± 0.6 | 9.8 ± 0.7 | 9.7 ± 0.7 |
VK + GP | 8.5 ± 1 | 9.3 ± 1.4 | 9.1 ± 1.2 | 12.1 ± 1.6 | 18.6 ± 3.9 *^ |
Von Frey test | |||||
[g] | |||||
VK | 27.4 ± 0.8 | 27.2 ± 0.7 | 27.4 ± 0.7 | 27 ± 0.7 | 26.6 ± 0.5 |
VK + GP | 27.2 ± 0.8 | 27.5 ± 0.6 | 27.8 ± 1.8 | 29.8 ± 1.1 *^ | 31.2 ± 0.7 *^ |
Intervention | t = 0 | t = 1 h | t = 2 h | t = 3 h | t = 6 h |
---|---|---|---|---|---|
[s] | |||||
VK + Gabapentin | 9.7 ± 0.7 | 10.1 ± 0.6 | 9.5 ± 0.6 | 9.8 ± 0.7 | 9.7 ± 0.7 |
VK + Extract D 5 mg/kg | 7.3 ± 0.9 | 22.8 ± 8.3 *^ | 17.7 ± 6.7 *^ | 22.9 ± 6.6 *^ | 19.3 ± 6.4 *^ |
VK + Extract D 7.5 mg/kg | 8.9 ± 0.9 | 20.4 ± 5.6 *^ | 21.1 ± 3.3 *^ | 18.2 ± 3.2 ^ | 17.6 ± 4.6 ^ |
VK + Extract D 10 mg/kg | 8.8 ± 0.9 | 20.5 ± 3.5 *^ | 15.1 ± 4.3 | 11.2 ± 1.9 | 18.5 ± 5.5 |
VK + Extract D 20 mg/kg | 8.8 ± 1.2 | 17.6 ± 2.4^ | 14.9 ± 2.3 | 12.7 ± 1.4 | 13.4 ± 1.3 |
VK + Extract D 40 mg | 7.9 ± 0.6 | 12.7 ± 2 | 11.6 ± 1.6 | 13.3 ± 2.1 | 15 ± 1.8 ^ |
VK + Extract B 5 mg/kg | 9.4 ± 1.1 | 17.2 ± 3.2 *^ | 13.7 ± 1.1 | 10.6 ± 1.0 | 10.7 ± 0.9 |
VK + Extract B 7.5 mg/kg | 9.0 ± 1.2 | 15.2 ± 4.4 ^ | 10.3 ± 1.0 | 9.2 ± 0.9 | 13.7 ± 3.7 |
VK + Extract B 10 mg/kg | 7.8 ± 1.0 | 10.3 ± 0.9 | 9.5 ± 0.6 *^ | 11.9 ± 1.2 | 12.1 ± 1.7 |
VK + Extract B 20 mg/kg | 6.3 ± 0.8 | 16.4 ± 5.5 *^ | 10.6 ± 1.1 | 15.6 ± 5.7 ^ | 15.4 ± 5.7 ^ |
VK + Extract B 40 mg/kg | 8.1 ± 1.0 | 9.0 ± 0.8 | 11.6 ± 1.0 | 9.8 ± 1.1 | 16.4 ± 3.6 *^ |
Grupa | t = 0 | t = 1 h | t = 2 h | t = 3 h | t = 6 h |
---|---|---|---|---|---|
[g] | |||||
VK + Gabapentin | 27.4 ± 0.8 | 27.2 ± 0.7 | 27.4 ± 0.7 | 27 ± 0.7 | 26.6 ± 0.5 |
VK + Extract D 5 mg/kg | 31 ± 1.8 | 28.9 ± 1.5 | 30.2 ± 1.0 | 29.6 ± 2.0 | 29.2 ± 1.6 |
VK + Extract D 7.5 mg/kg | 31.2 ± 1.8 * | 30.6 ± 1.3 | 30.9 ± 1.3 * | 33 ± 2.1 * | 28.2 ± 1.6 |
VK + Extract D 10 mg/kg | 31.4 ± 1.5 * | 33.3 ± 0.8 * | 30.8 ± 1.1 * | 29.6 ± 1.7 | 28.5 ± 0.9 |
VK + Extract D 20 mg/kg | 26.3 ± 1.3 | 32.5 ± 1.5 *^ | 26.2 ± 0.8 | 27.7 ± 1.2 | 27.5 ± 1.0 |
VK + Extract D 40 mg | 30.6 ± 0.8 | 34.8 ± 4.6 *^ | 28.7 ± 1.5 | 26.9 ± 1.5 ^ | 29.3 ± 1.8 |
VK + Extract B 5 mg/kg | 29.9 ± 1.3 | 31.2 ± 2.1 * | 29.3 ± 1.9 | 28.5 ± 1.2 | 29.6 ± 2.3 |
VK + Extract B 7.5 mg/kg | 27.9 ± 1.2 | 28.9 ± 1.2 | 29.3 ± 1.4 | 25.7 ± 2.0 | 25.3 ± 1.8 |
VK + Extract B 10 mg/kg | 30.2 ± 1.4 | 30.7 ± 2.0 | 31 ± 1.8 * | 29.3 ± 2.0 | 27.9 ± 1.5 |
VK + Extract B 20 mg/kg | 29.6 ± 1.5 | 30.8 ± 1.7 *^ | 34.8 ± 1.9 * | 32.1 ± 2.3 ^ | 26.1 ± 1.8 |
VK + Extract B 40 mg/kg | 29.2 ± 1.7 | 28.2 ± 0.8 | 29.9 ± 1.7 | 26.5 ± 0.7 | 26.2 ± 2.2 |
CB1R (Vincristine Group VK vs. NaCl Group) | |||||
---|---|---|---|---|---|
Intervention | Hippocampus | Cortex | Lymphocytes | ||
Protein [ng/mL] Median (1st; 3rd Quartile) | Gene Expression Median (1st; 3rd Quartile) | Protein [ng/mL] Median (1st; 3rd Quartile) | Gene Expression Median (1st; 3rd Quartile) | Gene Expression Median (1st; 3rd Quartile) | |
NaCl- 1 mL i.p. + Rape oil -1 mL p.o. | 1.45 (1.14; 2.69) | 3.04 × 10−3 (1.92 × 10−3; 5.25 × 10−3) | 3.99 (3.32; 4.57) | 21.20 × 10−3 (13.10 × 10−3; 84.20 × 10−3) | 0.03 × 10−3 (0.001 × 10−3; 0.87 × 10−3) |
VK +Rape oil—1 mL p.o. | 0.89 (0.39; 1.03) | 4.36 × 10−3 (2.92 × 10−3; 6.68 × 10−3) | 2.75 (2.36; 3.78) * | 22.90 × 10−3 (14.40 × 10−3; 35.40 × 10−3) | 0.02 × 10−3 (0.05 × 10−3; 0.16 × 10−3) |
CB2R (vincristine group VK vs. NaCl group) | |||||
NaCl- 1 mL i.p. + Rape oil -1 mL p.o. | 0.25 (0.18; 0.32) | 3.90 × 10−3 (2.21 × 10−3; 11.40 × 10−3) | 1.26 (1.02; 1.45) | 50.30 × 10−3 (13.80 × 10−3; 71.40 × 10−3) | 32.10 × 10−3 (14.60 × 10−3; 41.50 × 10−3) |
VK + Rape oil—1 mL p.o. | 0.29 (0.26; 0.55) | 3.45 × 10−3 (2.71 × 10−3; 4.56 × 10−3) | 0.87 (0.83; 0.97) | 3.18 × 10−3 * (1.67 × 10−3; 7.43 × 10−3) | 23.50 × 10−3 (18.70 × 10−3; 84.30 × 10−3) |
CB1R (vincristine group VK vs. gabapentin group) | |||||
VK + Rape oil—1 mL p.o. | 0.89 (0.39; 1.03) | 4.36 × 10−3 (2.92 × 10−3; 6.68 × 10−3) | 2.75 (2.36; 3.78) | 22.90 × 10−3 (14.40 × 10−3; 35.40 × 10−3) | 0.02 × 10−3 (0.05 × 10−3; 0.16 × 10−3) |
VK + Gabapentin-60 mg/kg p.o. | 2.51 (2.13; 2.8) ^ | 3.02 × 10−3 (1.14 × 10−3; 4.6 × 10−3) | 2.74 (2.09; 3.2) | 31.30 × 10−3 (26.50 × 10−3; 33.30 × 10−3) | 0.01 × 10−3 (0.001 × 10−3; 0.011 × 10−3) |
CB2R (vincristine group VK vs. gabapentin group) | |||||
VK +Rape oil—1 mL p.o. | 0.29 (0.26; 0.55) | 3.45 × 10−3 (2.71 × 10−3; 4.56 × 10−3) | 0.87 (0.83; 0.97) | 3.18 × 10−3 (1.67 × 10−3; 7.43 × 10−3) | 23.50 × 10−3 (18.70 × 10−3; 84.30 × 10−3) |
VK + Gabapentin-60 mg/kg p.o. | 0.42 (0.34; 0.5) | 4.79 × 10−3 (2.94 × 10−3; 13.80 × 10−3) | 1.25 (1.03; 1.40) | 2.35 × 10−3 (0.51 × 10−3; 3.63 × 10−3) | 35.30 × 10−3 (14.70 × 10−3; 57.10 × 10−3) |
CB1R | |||||
---|---|---|---|---|---|
Type of Intervention | Hippocampus | Cortex | Lymphocytes | ||
Protein [ng/mL] Median (1st; 3rd Quartile) | Gene Expression Median (1st; 3rd Quartile) | Protein [ng/mL] Median (1st; 3rd Quartile) | Gene Expression Median (1st; 3rd Quartile) | Gene Expression Median (1st; 3rd Quartile) | |
VK + Rape oil | 0.89 (0.39; 1.03) | 4.36 × 10−3 (2.92 × 10−3; 6.68 × 10−3) | 2.75 (2.36; 3.78) | 22.90 × 10−3 (14.40 × 10−3; 35.40 × 10−3) | 0.02 × 10−3 (0.05 × 10−3; 0.16 × 10−3) |
VK + Gabapentin | 2.51 (2.13; 2.8) | 3.02 × 10−3 (1.14 × 10−3; 4.6 × 10−3) | 2.74 (2.09; 3.2) | 31.30 × 10−3 (26.50 × 10−3; 33.30 × 10−3) | 0.01 × 10−3 (0.001 × 10−3; 0.011 × 10−3) |
VK + Extract D 5 mg/kg | 1.96 (1.44; 2.09) | 3.15 × 10−3 (1.45 × 10−3; 3.67 × 10−3) | 2.97 (1.74; 3.2) | 2.95 × 10−3 (2.21 × 103; 6.61 × 10−3) | 15 0.07 × 10−3 (0.01 × 10−3; 0.10 × 10−3) |
VK + Extract D 7.5 mg/kg | 2.4 (2.17; 3.8) | 5 1.73 × 10−3 (0.89 × 10−3; 2.43 × 10−3) | 6 3.4 (3.27; 4.2) | 11 439.90 × 10−3 (2.72 × 10−3; 1957 × 10−3) | 0.11 × 10−3 (0.06 × 10−3; 0.18 × 10−3) |
VK + Extract D 10 mg/kg | 1 3.26 (3.22; 4.06) | 9.97 × 10−3 (5.51 × 10−3; 14.7 × 10−3) | 7 4.35 (4.11; 5.15) | 5.51 × 10−3 (3.56 × 10−3; 5.51 × 10−3) | 0.64 × 10−3 (0.16 × 10−3; 1.08 × 10−3) |
VK + Extract D 20 mg/kg | 2.24 (1.71; 2.95) | 6.54 × 10−3 (0.37 × 10−3; 7.35 × 10−3) | 1.72 (1.06; 2.24) | 12 0.24 × 10−3 (0.03 × 10−3; 1.53 × 10−3) | 0.56 × 10−3 (0.03 × 10−3; 2.03 × 10−3) |
VK + Extract D 40 mg | 2 3.77 (2.78; 4.34) | 2.44 × 10−3 (0.89 × 10−3; 3.8 × 10−3) | 1.5 (1.35; 1.77) | 4.12 × 10−3 (2.34 × 10−3; 5.64 × 10−3) | 0.14 × 10−3 (0.01 × 10−3; 0.21 × 10−3) |
VK + Extract B 5 mg/kg | 1.24 (0.26; 2.65) | 1.57 × 10−3 (0.70 × 10−3; 5.85 × 10−3) | 1.53 (1.16; 1.64) | 13 1.14 × 10−3 (0.34 × 10−3; 2.22 × 10−3) | 0.26 × 10−3 (0.12 × 10−3; 0.74 × 10−3) |
VK + Extract B 7.5 mg/kg | 3 5.65 (3.22; 9.02) | 7.57 × 10−3 (5.19 × 10−3; 11.7 × 10−3) | 1.49 (1.19; 1.55) | 14 0.05 × 10−3 (0.001 × 10−3; 0.07 × 10−3) | 0.41 × 10−3 (0.11 × 10−3; 1.29 × 10−3) |
VK + Extract B 10 mg/kg | 4 3.6 (2.90; 5.00) | 8.12 × 10−3 (4.17 × 10−3; 12.0 × 10−3) | 8 0.6 (0.2; 1.0) | 11.16 × 10−3 (9.82 × 10−3; 19.30 × 10−3) | 0.27 × 10−3 (0.11 × 10−3; 0.54 × 10−3) |
VK + Extract B 20 mg/kg | 2.88 (2.70; 3.60) | 4.17 × 10−3 (3.41 × 10−3; 5.07 × 10−3) | 9 0.36 (0.34; 0.4) | 2.43 × 10−3 (1.73 × 10−3; 3.55 × 10−3) | 0.37 × 10−3 (0.11 × 10−3; 0.61 × 10−3) |
VK + Extract B 40 mg/kg | 2.44 (1.43; 3.38) | 7.99 × 10−3 (1.90 × 10−3; 9.59 × 10−3) | 10 0.75 (0.53; 1.01) | 3.77 × 10−3 (1.86 × 10−3; 5.46 × 10−3) | 0.02 × 10−3 (0.01 × 10−3; 0.04 × 10−3) |
Type of Intervention | CB2R | ||||
---|---|---|---|---|---|
Hippocampus | Cortex | Lymphocytes | |||
Protein [ng/mL] Median (1st; 3rd Quartile) | Gene Expression Median (1st; 3rd Quartile) | Protein [ng/mL] Median (1st; 3rd Quartile) | Gene Expression Median (1st; 3rd Quartile) | Gene Expression Median (1st; 3rd Quartile) | |
VK + Rape oil | 0.29 (0.26; 0.55) | 3.45 × 10−3 (2.71 × 10−3; 4.56 × 10−3) | 0.87 (0.83; 0.97) | 3.18 × 10−3 (1.67 × 10−3; 7.43 × 10−3) | 23.50 × 10−3 (18.70 × 10−3; 84.30 × 10−3) |
VK + Gabapentin | 0.42 (0.34; 0.5) | 4.79 × 10−3 (2.94 × 10−3; 13.80 × 10−3) | 1.25 (1.03; 1.40) | 2.35 × 10−3 (0.51 × 10−3; 3.63 × 10−3) | 35.30 × 10−3 (14.70 × 10−3; 57.10 × 10−3) |
VK + Extract D 5 mg/kg | 0.25 (0.22; 0.41) | 2.79 × 10−3 (2.02 × 10−3; 5.33 × 10−3) | 0.97 (0.87; 1.13) | 13.90 × 10−3 (6.15 × 10−3; 29.60 × 10−3) | 43.80 × 10−3 (32.70 × 10−3; 117.30 × 10−3) |
VK + Extract D 7.5 mg/kg | 0.4 (0.27; 0.50) | 2 7.87 × 10−3 (4.51 × 10−3; 22.9 × 10−3) | 1.00 (0.92; 1.10) | 27.90 × 10−3 (15.00 × 10−3; 49.70 × 10−3) | 59.00 × 10−3 (29.10 × 10−3; 79.60 × 10−3) |
VK + Extract D 10 mg/kg | 0.32 (0.29 0.41) | 1.49 × 10−3 (1.32 × 10−3; 3.72 × 10−3) | 3 1.06 (0.88; 1.42) | 6 3.24 × 10−3 (2.34 × 10−3; 7.20 × 10−3) | 61.50 × 10−3 (52.40 × 10−3; 91.90 × 10−3) |
VK + Extract D 20 mg/kg | 0.25 (0.12; 0.29) | 2.39 × 10−3 (0.35 × 10−3; 7.03 × 10−3) | 0.76 (0.71; 0.88) | 45.50 × 10−3 (13.50 × 10−3; 97.20 × 10−3) | 60.10 × 10−3 (39.80 × 10−3; 73.10 × 10−3) |
VK + Extract D 40 mg | 0.39 (0.34; 0.44) | 5.73 × 10−3 (1.36 × 10−3; 8.47 × 10−3) | 0.34 (0.25; 0.72) | 5.50 × 10−3 (4.00 × 10−3; 15.50 × 10−3) | 38.20 × 10−3 (32.00 × 10−3; 84.60 × 10−3) |
VK + Extract B 5 mg/kg | 0.32 (0.22; 0.45) | 2.31 × 10−3 (1.06 × 10−3; 3.02 × 10−3) | 0.27 (0.13; 0.41) | 14.50 × 10−3 (6.01 × 10−3; 27.70 × 10−3) | 29.20 × 10−3 (15.40 × 10−3; 73.80 × 10−3) |
VK + Extract B 7.5 mg/kg | 1 1.39 (0.83; 1.52) | 0.27 × 10−3 (0.20 × 10−3; 0.42 × 10−3) | 0.10 (0.08; 0.17) | 0.32 × 10−3 (0.001 × 10−3; 0.13 × 10−3) | 37.40 × 10−3 (25.30 × 10−3; 47.40 × 10−3) |
VK + Extract B 10 mg/kg | 0.8 (0.70; 1.00) | 0.30 × 10−3 (0.16 × 10−3; 0.48 × 10−3) | 4 0.10 (0.01; 0.19) | 1.62 × 10−3 (0.99 × 10−3; 1.87 × 10−3) | 63.80 × 10−3 (31.70 × 10−3; 72.50 × 10−3) |
VK + Extract B 20 mg/kg | 0.94 (0.73; 1.10) | 1.51 × 10−3 (0.53 × 10−3; 3.40 × 10−3) | 5 0.05 (0.04; 0.10) | 1.53 × 10−3 (1.21 × 10−3; 2.89 × 10−3) | 24.00 × 10−3 (19.30 × 10−3; 38.60 × 10−3) |
VK + Extract B 40 mg/kg | 0.92 (0.54; 1.02) | 5.82 × 10−3 (1.36 × 10−3; 6.96 × 10−3) | 0.09 (0.07; 0.12) | 1.00 × 10−3 (0.65 × 10−3; 1.34 × 10−3) | 48.20 × 10−3 (42.00 × 10−3; 54.90 × 10−3) |
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Bartkowiak-Wieczorek, J.; Bienert, A.; Czora-Poczwardowska, K.; Kujawski, R.; Szulc, M.; Mikołajczak, P.; Wizner, A.-M.; Jamka, M.; Hołysz, M.; Wielgus, K.; et al. Cannabis sativa L. Extract Alleviates Neuropathic Pain and Modulates CB1 and CB2 Receptor Expression in Rat. Biomolecules 2024, 14, 1065. https://doi.org/10.3390/biom14091065
Bartkowiak-Wieczorek J, Bienert A, Czora-Poczwardowska K, Kujawski R, Szulc M, Mikołajczak P, Wizner A-M, Jamka M, Hołysz M, Wielgus K, et al. Cannabis sativa L. Extract Alleviates Neuropathic Pain and Modulates CB1 and CB2 Receptor Expression in Rat. Biomolecules. 2024; 14(9):1065. https://doi.org/10.3390/biom14091065
Chicago/Turabian StyleBartkowiak-Wieczorek, Joanna, Agnieszka Bienert, Kamila Czora-Poczwardowska, Radosław Kujawski, Michał Szulc, Przemysław Mikołajczak, Anna-Maria Wizner, Małgorzata Jamka, Marcin Hołysz, Karolina Wielgus, and et al. 2024. "Cannabis sativa L. Extract Alleviates Neuropathic Pain and Modulates CB1 and CB2 Receptor Expression in Rat" Biomolecules 14, no. 9: 1065. https://doi.org/10.3390/biom14091065