Cremaphor

THC stock solution (100 mg/mL in ethanol) was obtained from the U.S. National Institute on Drug Abuse. Ethanol was evaporated using nitrogen gas and the remaining THC was re-dissolved in dimethysulfoxide (DMSO) and aliquoted for storage at −20^C. THC at the various doses used in these studies was made fresh before each administration in a vehicle consisting of 1:1:18 (DMSO : Cremaphor : 0.9% Saline) (Cat# D2650 and C5135 for DMSO and Cremaphor EL, respectively, Sigma Aldrich, St. Louis, MO).

The production and synthesis of VSN16 (318 Da) and the VSN16R and VSN16S enantiomers and VSN22 were as described previously (Hoi et al.,2007). VSN44 was also synthesized (Supporting Information Methods S1). These compounds were additionally synthesized to either Good Manufacturing Practice or Good Laboratories Practice Standards by Sygnature Chemical Services (Nottingham, UK), Park Place Research (Cardiff, UK) or Dalton Chemical Laboratories Inc. (Toronto, Canada). VSN16R for human use was formulated in 25 and 100 mg gelatin capsules by Dalton Chemical Laboratories. R(+)WIN55‐212 was purchased from Tocris Ltd. (Bristol, UK) and ±baclofen was purchased from Sigma Aldrich Ltd (Poole, UK). 1′, 1′‐dimethylheptyl‐M8‐tetrahydrocannabinol‐11‐oic acid (CT3) was supplied by Atlantic Ventures Inc. (New York, USA) (Pryce et al.,2014). BMS‐204352; NS‐1619, NS‐11021, paxilline and CNQX were purchased from Tocris Ltd or Sigma (Poole, UK). Compounds were dissolved in water; saline or DMSO (WIN55‐212) or ethanol prior to dilution with cremaphor (Sigma) and PBS (1:1:18). These drugs were delivered via the p.o., i.p. or i.v. routes at less than 5 mL·kg⁻¹, typically 0.1 mL in mice and 0.5 mL in rats. Although VSN16R is water soluble (>30 mg·mL⁻¹), for higher concentrations (200 mg·mL⁻¹), it was dissolved in 20% polypropylene in water.

A stock solution of PTX (Tocris Bioscience; 15mg/ml) was prepared in Cremaphor (Sigma Aldrich) and ethanol in a 1:1 ratio and further diluted in 0.9% sterile saline to a final injected dose of 5mg/kg in 50μL/mouse. A stock solution of OXA (Sigma-Aldrich; 5 mg/ml) was prepared in 0.9% saline and further diluted with sterile saline at a 1:1 ratio to a final injected dose of 5mg/kg in 50μL/mouse. Mice were injected on alternate days (days 0, 2, 4, 6) intraperitoneally (i.p.) with a cumulative dose of 20mg/kg (equals 740mg/m² in humans) distributed over 4 injection cycles. Control mice were injected i.p. with 50μL of 0.9% sterile saline over 4 alternating days to match the injection volume and cycle of the chemotherapy drugs.