Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice

Abstract

Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of these agonists is known to produce enhanced antinociception in several rodent models of acute and chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination, using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; and (c) hot plate thermal nociception. Morphine alone produced antinociceptive effects in all three models of acute nociception, whereas CBD alone produced antinociception only in the acetic acid-stimulated stretching assay. The nature of the interactions between morphine and CBD combinations were assessed quantitatively based on the principle of dose equivalence. Combinations of CBD and morphine produced synergistic effects in reversing acetic acid-stimulated stretching behavior, but subadditive effects in the hot plate thermal nociceptive assay and the acetic acid-decreased operant responding for palatable food assay. These results suggest that distinct mechanisms of action underlie the interactions between CBD and morphine in the three different behavioral assays and that the choice of appropriate combination therapies for the treatment of acute pain conditions may depend on the underlying pain type and stimulus modality.

Effects of Cannabidiol and a Novel Cannabidiol Analog against Tactile Allodynia in a Murine Model of Cisplatin-Induced Neuropathy: Enhanced Effects of Sub-Analgesic Doses of Morphine

“…While literature exists that demonstrates an analgesic synergy between CBD and morphine in models of inflammatory pain [18], this is the first report in the literature to describe such findings generalizable to a murine model of CIN.…”

“…Interestingly, other CB that show low affinity to CB receptors also show synergistic effects with low dose opioids. For example, cannabidiol (CBD) shows synergistic effects with sub-analgesic doses of morphine in an acute pain model (i.e., acetic acid writhing) but not against thermal pain [18]. Whether a combined CBD-opioid or a bioengineered synthetic analogue of CBD-opioid pharmacotherapy could provide highly efficacious pain relief against CIN is unknown.…”

Effects of nicotine in combination with drugs described as positive allosteric nicotinic acetylcholine receptor modulators in vitro: discriminative stimulus and hypothermic effects in mice

“…Neelakantan et al, 2015) was used to evaluate the combined effects of nicotine and an allosteric modulator on rectal temperature. The change in rectal temperature at 30 min following 32 mg/kg dFBr and 100 mg/kg PNU-120596 was substituted into the non-linear regression equation calculated for the nicotine dose-response function and solved for dose; this yielded the dose of nicotine required to produce the effect obtained at 32 mg/kg dFBr and 100 mg/kg PNU-120596, i.e.…”

A nutraceutical role for cannabidiol. Why not?

“…Morphine alone produced anti-nociceptive effects in all three models of acute nociception, whereas CBD alone produced anti-nociception only in the acetic acid-stimulated stretching assay. Combinations of CBD and morphine produced synergistic effects in reversing acetic acidstimulated stretching behaviour but sub-additive effects in the hot plate thermal nociceptive assay [15].…”