Tolerance to hypothermic and antinoceptive effects of ∆9-tetrahydrocannabinol (THC) vapor inhalation in rats

Pharmacol Biochem Behav. 2018 Sep;172:33-38. doi: 10.1016/j.pbb.2018.07.007. Epub 2018 Jul 19.


Rationale: A reduced effect of a given dose of ∆9-tetrahydrocannabinol (THC) emerges with repeated exposure to the drug. This tolerance can vary depending on THC dose, exposure chronicity and the behavioral or physiological measure of interest. A novel THC inhalation system based on e-cigarette technology has been recently shown to produce the hypothermic and antinociceptive effects of THC in rats.

Objective: To determine if tolerance to these effects can be produced with repeated vapor inhalation.

Methods: Groups of male and female Wistar rats were exposed to 30 min of inhalation of the propylene glycol (PG) vehicle or THC (200 mg/mL in PG) two or three times per day for four days. Rectal temperature changes and nociception were assessed after the first exposure on the first and fourth days of repeated inhalation.

Results: Female, but not male, rats developed tolerance to the hypothermic and antinociceptive effects of THC after four days of twice-daily THC vapor inhalation. Thrice daily inhalation for four days resulted in tolerance in both male and female rats. The plasma THC levels reached after a 30 min inhalation session did not differ between the male and female rats.

Conclusions: Repeated daily THC inhalation induces tolerance in female and male rats, providing further validation of the vapor inhalation method for preclinical studies.

Keywords: Cannabis; E-cigarette; Hypothermia; Marijuana; Nociception; Tolerance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Inhalation
  • Analgesics, Non-Narcotic / administration & dosage
  • Analgesics, Non-Narcotic / pharmacokinetics
  • Analgesics, Non-Narcotic / pharmacology*
  • Animals
  • Dronabinol / administration & dosage
  • Dronabinol / pharmacokinetics
  • Dronabinol / pharmacology*
  • Drug Tolerance
  • Electronic Nicotine Delivery Systems
  • Female
  • Hypothermia / chemically induced*
  • Hypothermia, Induced
  • Male
  • Nociception / drug effects*
  • Rats
  • Rats, Wistar
  • Sex Factors


  • Analgesics, Non-Narcotic
  • Dronabinol