PT  - JOURNAL ARTICLE
AU  - Benjamin M Ford
AU  - Christian V Cabanlong
AU  - Sherrica Tai
AU  - Lirit N Franks
AU  - Narsimha Reddy Penthala
AU  - Peter A Crooks
AU  - Paul L Prather
AU  - William E Fantegrossi
TI  - Reduced tolerance and asymmetrical cross-tolerance to effects of indole quinuclidinone analogue PNR-4-20, a G protein biased CB1R agonist in mice: comparisons with Δ9-THC and JWH-018
AID  - 10.1124/jpet.118.252965
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.118.252965
4099  - http://jpet.aspetjournals.org/content/early/2019/03/04/jpet.118.252965.short
4100  - http://jpet.aspetjournals.org/content/early/2019/03/04/jpet.118.252965.full
AB  - Most cannabinoid CB1 receptor (CB1R) agonists signal through both G protein-dependent and -independent pathways in an unbiased manner. Recruitment of β-arrestin 2 desensitizes and internalizes receptors, producing tolerance which limits therapeutic utility of cannabinoids for chronic conditions. We developed the indole quinuclidinone (IQD) analogue PNR-4-20 as a novel G protein-biased agonist at CB1Rs, and the present studies determine if repeated administration of PNR-4-20 produces lesser tolerance to in vivo effects as compared to unbiased CB1R agonists Δ9-THC and JWH-018. Adult male NIH Swiss mice were administered comparable doses of PNR-4-20 (100 mg/kg), Δ9-THC (30 mg/kg) or JWH-018 (3 mg/kg) once per day for 5 consecutive days in order to determine tolerance development to hypothermic, antinociceptive and cataleptic effects. Persistence of tolerance was then determined after a drug abstinence period. We found that unbiased CB1R agonists Δ9-THC and JWH-018 produced similar tolerance to these effects, but lesser tolerance was observed with PNR-4-20 for hypothermic and cataleptic effects. Tolerance to the effects of PNR-4-20 completely recovered after drug abstinence, while residual tolerance was always observed with unbiased CB1R agonists. Repeated treatment with PNR-4-20 and Δ9-THC produced asymmetrical cross-tolerance to hypothermic effects. Importantly, binding studies suggest PNR-4-20 produced significantly less downregulation of CB1Rs relative to Δ9-THC in hypothalamus and thalamus of chronically treated mice. These studies suggest that the G protein-biased CB1R agonist PNR-4-20 produces significantly less tolerance than unbiased cannabinoid agonists, and that the IQD analogues should be investigated further as a novel molecular scaffold for development of new therapeutics.