Premium
The Sigma 1 Receptor Antagonist CM304 Potentiates the Antinociceptive but not the Discriminative Stimulus Effects of the Cannabinoid Receptor Agonist THC in Rats
Author(s) -
Obeng Samuel,
Patel Avi,
Burns Mallory,
Intagliata Sebastiano,
Mottinelli Marco,
Reeves Morgan E.,
Behnke Mira,
Restrepo Luis F.,
Ho Nicholas P.,
Gamez Jimenez Lea R.,
Williamson Morgan R.,
McCurdy Christopher R.,
McMahon Lance R.,
Hiranita Takato
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05381
Subject(s) - rimonabant , pharmacology , cannabinoid , agonist , antagonist , opioid , cannabinoid receptor agonists , chemistry , receptor antagonist , cannabinoid receptor antagonist , medicine , cannabinoid receptor , nociception , receptor
Opioid overdose is one of the leading causes of death in the United States in people under 50 years, which has resulted in a decline in life expectancy in the United States. Thus, there is a need for an alternative to prescription mu‐opioid agonists for pain treatment. Delta (9)‐tetrahydrocannabinol (THC), a cannabinoid (CB) agonist, has been shown to produce antinociceptive effects albeit less effectively than mu‐opioid receptor agonists. Sigma 1 receptor (σ 1 R) antagonists in combination with THC may provide a viable and safe pharmacological alternative to prescription opioids for pain treatment. The present study compared the pharmacological effects of the σ 1 R antagonist CM304 alone and in combination with THC in Sprague Dawley rats. Hotplate latency was determined at 52°C followed by rectal temperature measurement and the drugs were administered intravenously (i.v.) and in cumulative doses every 5 min. THC dose‐dependently increased maximum possible effects (MPEs) up to 84% which were reversed by 10 mg/kg rimonabant (cannabinoid CB 1 receptor antagonist). CM304 alone up to a dose of 10 mg/kg did not produce significant antinociceptive or hypothermic effects, but CM304 (1.0 and 3.2 mg/kg, i.v.) dose‐dependently left‐shifted the dose‐effect functions of the antinociceptive (7.3‐fold at 3.2 mg/kg CM304) and hypothermic effects of THC. In rats discriminating 3.2 mg/kg THC i.p. from vehicle under a fixed ratio (FR) 10 schedule of food delivery, the cannabinoid CB 1 receptor agonist CP55,940 fully substituted for THC, whereas CM304 i.p. produced a maximum of 27 % THC‐lever responding at 17.8 mg/kg. CM304, at doses of 32 and 56 mg/kg, decreased response rate to 24 and 9 %, respectively. No dose of BD1063 (σ 1 R antagonist), rimonabant, SR144528 (cannabinoid CB 2 receptor antagonist), morphine (μ‐opioid receptor agonist), or naltrexone (opioid antagonist) produced greater than 30% THC‐lever responding. Pretreatment with rimonabant (1.78 mg/kg) produced a rightward shift in the dose effect curve of THC (4.5‐fold) and CP55940 (4.5‐fold) while pretreatment with CM304, BD1063, SR144528, and naltrexone had no significant effect on the dose effect curve of THC. The present results may support the development of a σ 1 R antagonist as an adjunct to cannabinoids for treatment of acute pain without enhancing an undesirable side effect of THC. Support or Funding Information This work was supported by National Institute on Drug Abuse grants DA23205 and DA48353.