PMID- 36394060
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221119
IS  - 1178-7090 (Print)
IS  - 1178-7090 (Electronic)
IS  - 1178-7090 (Linking)
VI  - 15
DP  - 2022
TI  - The Endocannabinoid Analgesic Entourage Effect: Investigations in Cultured DRG 
      Neurons.
PG  - 3493-3507
LID - 10.2147/JPR.S378876 [doi]
AB  - BACKGROUND: The endocannabinoid 2-Arachidonyl glycerol (2-AG) exerts dose-related 
      anti-nociceptive effects, which are potentiated by the related but inactive 
      2-palmitoyl glycerol (2-PG) and 2-linoleoyl glycerol (2-LG). This potentiation of 
      analgesia and other in vivo measures was described as the "entourage effect". We 
      investigated this effect on TRPV1 signalling in cultured dorsal root ganglion 
      (DRG) nociceptors. METHODS: Adult rat DRG neurons were cultured in medium 
      containing NGF and GDNF at 37 degrees C. 48 h later cultures were loaded with 2 microM 
      Fura2AM for calcium imaging, and treated with 2-AG, 2-PG and 2-LG, individually 
      or combined, for 5 min, followed by 1 microMol capsaicin. The amplitude and latency 
      of capsaicin responses were measured (N=3-7 rats, controls N=16), and analysed. 
      RESULTS: In controls, 1 microMol capsaicin elicited immediate calcium influx in a 
      subset of neurons, with average latency of 1.27 +/- 0.2 s and amplitude of 0.15 +/- 
      0.01 Units. 2-AG (10-100 microMol) elicited calcium influx in some neurons. In the 
      presence of 2-AG (0.001-100 microMol), capsaicin responses were markedly delayed in 
      64% neurons by up to 320 s (P<0.001). 2-PG increased capsaicin response latency 
      at 0.1 nMol-100 microMol (P<0.001), in 60% neurons, as did 2-LG at 0.1-100 microMol 
      (P<0.001), in 76% neurons. Increased capsaicin response latency due to 2-AG and 
      2-PG was sensitive to the CB(2) but not to the CB(1) receptor antagonist. 
      Combined application of 1 microMol 2-AG, 5 microMol 2-PG and 10 microMol 2-LG, also resulted 
      in significantly increased capsaicin response latency up to 281.5 +/- 41.5 s 
      (P<0.001), in 96% neurons, that was partially restored by the CB(2), but not the 
      CB(1) antagonist. CONCLUSION: 2-AG, 2-LG and 2-PG significantly delayed TRPV1 
      signalling in the majority of capsaicin-sensitive DRG neurons, that was markedly 
      increased following combined application. Further studies of these 
      endocannabinoids are required to identify the underlying mechanisms.
CI  - (c) 2022 Anand et al.
FAU - Anand, Uma
AU  - Anand U
AUID- ORCID: 0000-0002-3704-4600
AD  - Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial 
      College London, London, W12 0HS, UK.
FAU - Pacchetti, Barbara
AU  - Pacchetti B
AD  - Curaleaf International Limited, London, EC2A 2EW, UK.
FAU - Anand, Praveen
AU  - Anand P
AD  - Professor of Clinical Neurology, Department of Brain Sciences, Imperial College 
      London, London, W12 0HS, UK.
FAU - Sodergren, Mikael Hans
AU  - Sodergren MH
AD  - Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial 
      College London, London, W12 0HS, UK.
AD  - Curaleaf International Limited, London, EC2A 2EW, UK.
LA  - eng
PT  - Journal Article
DEP - 20221104
PL  - New Zealand
TA  - J Pain Res
JT  - Journal of pain research
JID - 101540514
PMC - PMC9642605
OTO - NOTNLM
OT  - DRG neurons
OT  - analgesia
OT  - endocannabinoids
OT  - entourage effect
OT  - nociception
COIS- MHS received a grant to support this research and he is a consultant at Curaleaf 
      International. BP is Chief Scientific Officer (employee) at Curaleaf 
      International. The funders had no role in study design, data collection and 
      analysis, decision to publish, or preparation of the manuscript. The authors 
      report no other conflicts of interest in this work.
EDAT- 2022/11/18 06:00
MHDA- 2022/11/18 06:01
PMCR- 2022/11/04
CRDT- 2022/11/17 13:13
PHST- 2022/06/30 00:00 [received]
PHST- 2022/10/08 00:00 [accepted]
PHST- 2022/11/17 13:13 [entrez]
PHST- 2022/11/18 06:00 [pubmed]
PHST- 2022/11/18 06:01 [medline]
PHST- 2022/11/04 00:00 [pmc-release]
AID - 378876 [pii]
AID - 10.2147/JPR.S378876 [doi]
PST - epublish
SO  - J Pain Res. 2022 Nov 4;15:3493-3507. doi: 10.2147/JPR.S378876. eCollection 2022.