Differential Effects of Cannabidiol and a Novel Cannabidiol Analog on Oxycodone Place Preference and Analgesia in Mice: an Opioid Abuse Deterrent with Analgesic Properties

Abstract

Background and Purpose:

This study sought to determine whether cannabidiol (CBD) or a CBD derivative, CBD monovalinate monohemisuccinate (CBD-val-HS), could attenuate the development of oxycodone reward while retaining its analgesic effects.

Experimental Approach:

To determine the effect on oxycodone reward, animals were enrolled in the conditioned place preference paradigm and received either saline or oxycodone (3.0 mg/kg) in combination with either CBD or CBD-val-HS utilizing three sets of drug-/no drug-conditioning trials. To determine if the doses of CBD or CBD-val-HS that blocked opioid reward would affect nociceptive processes, animals were enrolled in the hot plate and abdominal writhing assays when administered alone or in combination with a subanalgesic (1.0 mg/kg) or analgesic (3.0 mg/kg) dose of oxycodone.

Key Results:

Results from condition place preference demonstrated CBD was not able attenuate oxycodone place preference while CBD-val-HS attenuated these rewarding effects at 8.0 mg/kg and was void of rewarding or aversive properties. In contrast to CBD, CBD-val-HS alone produced analgesic effects in both nociceptive assays but was most effective compared with oxycodone against thermal nociception. Of interest, there was a differential interaction of CBD and CBD-val-HS×oxycodone across the two nociceptive assays producing subadditive responses on the hot plate assay, whereas additive responses were observed in the abdominal writhing assay.

Conclusion:

These findings suggest CBD-val-HS alone, a nonrewarding analgesic compound, could be useful in pain management and addiction treatment settings.

Introduction

Opioids are considered the “gold standard” in pain management.¹ Although highly efficacious across pain conditions, opioids are not without shortcomings. Approximately 80% of patients treated with opioids suffer from adverse side effects that include sedation, vomiting, respiratory depression, and nausea.^2,3 Although such side effects diminish quality of life, a greater concern is that opioids possess a significant abuse liability.⁴

In 2017, an estimated 1.7 million Americans suffered from substance abuse disorders often resulting from prescription opioid use. In the same period, opioid overdoses resulted in ∼47,000 deaths.^5,6 This opioid crisis has led efforts to develop either opioid-based analgesic formulations with abuse-deterrent properties or nonopioid analgesics void of abuse liability.^7–9 The former strategy has shown success in pre-clinical models but, to date, has poor translational relevance. Previous research from our laboratory used the latter strategy and entails isolating active constituents from natural products traditionally used for treating pain conditions.¹⁰

Cannabis sativa has been used for more than four centuries as an analgesic for a variety of pain conditions.^11,12 The cannabis constituents Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) possess analgesic activity in pre-clinical and clinical pain syndromes.^10,13–16 However, neither produce analgesic effects as robust as opioids and this may be because of their poor bioavailability.¹⁷

An effort from this laboratory has been to develop cannabinoid prodrugs and analogs that address such concerns. One such compound is CBD monovalinate monohemisuccinate (CBD-val-HS), a CBD analog that shows better bioavailability and anti-nociception than CBD and, interestingly, analgesia equivalent to morphine in a murine model of chemotherapy-induced neuropathy.^18,19 Whether CBD-val-HS has analgesic activity beyond this neuropathic model is yet unknown.

In addition to its role in pain modulation, there is evidence that CBD modulates mechanisms of reward. For example, CBD facilitates the extinction of cocaine in the conditioned place preference (CPP) paradigm and blocks cued reinstatement in a CPP model of relapse.²⁰ CBD also attenuates the effects of morphine on response patterns of intracranial self-stimulation.²¹ These effects were reversed by pretreatment of a 5-HT_1A antagonist suggesting CBD mediates the rewarding properties of opioids through 5-HT_1A receptors located in the dorsal raphe.

Although the mechanism of action is not well understood, CBD has also shown to modulate negative side effects of CB1 agonists through negative allosteric modulation of the CB1 receptor.²² CBD has also shown to be a negative allosteric modulator at mu- and delta-opioid receptors and could potentially play a role in modulating the rewarding effects of opioids.²³ Previous work from our laboratory has shown that CBD blocks the development of morphine reward in the CPP paradigm.²⁴ Such observations suggest that CBD, and possibly the analog CBD-val-HS, may have abuse-deterrent properties as stand-alone analgesics or in opioid formulations, in pain management settings.

Materials and Methods

Animals

C57BL/6 male mice (25–30 g) were group housed (n=5) in a polycarbonate tub with soft bedding in a temperature and humidity-controlled vivarium. Mice were maintained under a 12:12 hour light/dark cycle with lights on at 06:00 hours. Food and water were available ad libitum. Mice acclimated to the vivarium colony room 1 week before behavioral testing and were allowed to acclimate to the testing room 30 min before behavioral testing. All experimental procedures were approved by the Institutional Animal Care Committee at the University of Mississippi (Protocol Nos. 15-022 and 19-009). This research complies with the 3Rs in animal research: Replacement, Reduction, and Refinement.

Drugs

Oxycodone (Tocris, Boston, MA) was dissolved in 0.9% saline to yield a dosage of 3.0 mg/mL. CBD and CBD-val-HS (ElSohly Laboratories; Oxford, MS) were dissolved in a solution of 10% ethanol/10% cremophore and 80% injectable water. Mice received sequential, dual IP injections of test compounds in a volume of 1.0 mL/kg. Doses of CBD-val-HS used in CPP were chosen based on prior studies in this laboratory.^17,18 CBD doses were calculated to be the dose equivalent of these doses. Doses of CBD-val-HS and CBD used in the nociceptive assays were based off of the dose that decreased oxycodone reward in the CPP paradigm.

Condition place preference

Condition place preference chambers (Model MED-CPP-3013; Med Associates, St. Albans, VT) were used to quantify reward or aversion. Each chamber has two stimulus-distinct conditioning chambers (black vs. white-colored walls and wire vs. mesh metal rod flooring; 16.75×12.70 cm) separated by a third central start chamber (7.25×12.70 cm; colored gray with a smooth solid floor). Guillotine doors permitted confinement/access to individual chambers. Before behavioral testing, animals were allowed to acclimate to the testing room for at least 30 min.

The CPP procedure consists of four phases: (1) a 15-min apparatus habituation trial, (2) a 15-min trial to establish baseline CPP scores, (3) six 45-min drug-conditioning trials, and (4) a 15-min trial to establish postconditioning CPP score.

During the drug-free habituation, baseline, and final preference trials animals were placed in the gray start chamber for a 5-min adaption period. After the adaption period, the guillotine doors were lifted allowing access to the entire apparatus. The test apparatus was thoroughly cleaned with 70% ethanol solution after each trial. Animals were injected with test compounds then immediately placed in testing chambers for all conditioning trials.

CPP scores were determined by $\frac{T i m e i n B l a c k}{T i m e i n B l a c k + W h i t e}$ and led to the establishment of the S+ chamber for drug conditioning, whereby S+ was assigned to the nonpreferred compartment. From these CPP scores, baseline and postconditioning scores were quantified as $\frac{T i m e i n S +}{T i m e i n S + + S -}$ . Preference scores were calculated by subtracting postconditioning and baseline CPP scores with positive values reflecting reward and negative values reflecting aversion. Baseline preference scores before conditioning revealed our chambers were unbiased as there was no significant preference to any of the test chambers. Methodology used in this study is based on previous studies evaluating cannabinoids and opioids in the condition place preference paradigm.^24,25

Hot plate

The hot plate (Model No. 52–8570; Harvard Instruments) was used to quantify thermal nociception. This consisted of an open top acrylic enclosure (12.7×15.24 cm) positioned on a plate heated set to 52°C. Test compounds were administered IP 30 min before behavioral testing. Mice were placed onto the hot plate and immediately removed following a nociceptive response (i.e., hind paw flutter, hind paw lick, or an escape response). A 45-sec cutoff was used to prevent tissue damage. The latency of a withdrawal response served as the dependent measure.

After testing on the hot plate, animals were given a no-drug/test-free week and then enrolled into acetic acid writhing assay. Methodology used in this study is based on previous studies evaluating compounds in the hot plate assay.²⁶

Abdominal writhing

Abdominal writhing testing was used to quantify inflammatory nociception. Testing was conducted in clear, open-top, acrylic observation chambers (12.7×15.24 cm) located on a smooth surface. Test compounds were administered IP 30 min before behavioral testing. For testing, mice were then given an IP injection of 0.7% acetic acid in a volume of 10.0 mL/1 kg and immediately placed in an observation chamber for 30-min test. The number of abdominal writhes served as the dependent measure. Methodology used in this study is based on previous studies evaluating the interaction of opioids and cannabinoids in the abdominal writhing assay.²⁷

Statistical analyses

Data were analyzed using SPSS software using two-way (between and within group) analysis of variance (ANOVA) and one-way (between groups) ANOVA for simple-effects analyses. If main effects or interactions were significant, data were further analyzed by one-way ANOVA and Fisher's LSD post hoc tests. Significance was set at p<0.05. In cases of unequal variances (assessed by Levene's test), data were transformed and analyzed using a square-root transformation.

Subadditive responses were defined by drug interactions in which the effect of a combination of two or more drugs with similar actions is less than the individual effects of the same drugs given alone. Subadditive responses were determined by Fisher's LSD post hoc analysis of individual drugs compared with the combination of two drugs administered in combination (see Supplementary Tables S1–S6 for statistical analysis for each assay).

Results

Condition place preference

The effects of CBD on oxycodone CPP scores are summarized in Figure 1. Preference scores were near zero in the control group (vehicle+saline) indicating there was little change between baseline and postconditioning CPP scores. Oxycodone-treated animals showed higher preference scores compared with the control group, indicative of reward. Across the saline groups, CBD did not show place preference, but place aversion was demonstrated at the highest dose tested. Among the oxycodone groups, CBD failed to decrease preference scores.

FIG. 1.

Effects of CBD on oxycodone place preference scores. Values represent difference in the mean ratio of time (seconds) spent in the S+ (drug-paired) chamber during pre- and postcondition trials. Open bars reflect saline-treated animals and striped bars represent morphine-treated animals. A two- and one-way ANOVA with Fisher's LSD post hoc analysis was used to analyze these data. *Significant difference from the vehicle group. Sample sizes were n=10. ANOVA, analysis of variance; CBD, cannabidiol.

A two-way ANOVA of these CPP data revealed a significant main effect for CBD and oxycodone (F(4, 90)=2.987, p=0.023; F(1, 90)=24.195, p<0.001, respectively). The interaction term for oxycodone×CBD was not significant (F(4, 90)=0.710, p=0.58). To determine whether oxycodone possessed place preference, a one-way ANOVA of the vehicle groups were conducted and revealed a significant effect for oxycodone (F(1, 18)=7.557, p=0.023).

To test whether CBD possessed rewarding or aversive properties, a one-way ANOVA among the saline groups was conducted and revealed a significant treatment effect (F(4, 45)=2.866, p=0.034). Planned comparisons among the saline groups were conducted and revealed a significant decrease in preference scores at the 10.0 mg/kg dose CBD, indicative of place aversion (p=0.009).

To determine whether CBD attenuated opioid reward, a one-way ANOVA on the oxycodone groups was conducted and failed to reveal a significant treatment effect (F(4, 45)=1.067, p=0.384). Planned comparisons among the oxycodone groups showed increased doses of CBD did not significantly decrease preference scores (p>0.101).

The effects of CBD-val-HS on oxycodone CPP scores are given in Figure 2. Preference scores were near zero in the control group (vehicle+saline) indicating there was little change between baseline and postconditioning CPP scores. Oxycodone-treated animals showed higher preference scores compared with the control group, indicative of reward. Across the saline groups, CBD-val-HS did not show place preference or aversion. Among the oxycodone groups, CBD-val-HS dose dependently decreased preference scores with a maximum effect at 8 mg/kg.

FIG. 2.

Effects of CBD-val-HS on oxycodone place preference scores. Values represent difference in mean ratio of time (seconds) spent in the S+ (drug-paired) chamber during pre-and postcondition trials. Opens bars reflect saline-treated animals and hatched bars represent oxycodone-treated animals. A two- and one-way ANOVA with Fisher's LSD post hoc analysis was used to analyze these data. *Significant difference from the vehicle group. ^†Significant attenuation of oxycodone preference. Sample sizes were n=11–15.

A two-way ANOVA of these CPP data revealed a significant main effect for CBD-val-HS and the CBD-val-HS×oxycodone interaction (F(4, 129)=1.203, p=0.025; F(4, 129)=1.541, p=0.32, respectively). The main effect for oxycodone was not significant (F(1, 129)=16.331, p=0.337). To determine whether oxycodone possessed place preference, a one-way ANOVA of the vehicle groups were conducted and revealed a significant effect for oxycodone (F(1, 24)=10.784, p=0.003).

To test whether CBD-val-HS possessed rewarding or aversive properties, a one-way ANOVA among the saline groups found no significant treatment effect (F(4, 66)=1.461, p=0.224). To determine whether CBD-val-HS attenuated opioid reward, a one-way ANOVA on the oxycodone groups found no significant treatment effect (F(4, 63)=1.22, p=0.310). Planned comparisons among the oxycodone groups found 8.0 mg/kg CBD-val-HS had significantly lower preference scores than vehicle (p=0.033).

Hot plate

The effects of oxycodone on CBD on hot plate responses are summarized in Figure 3. Vehicle and the subanalgesic dose of oxycodone (1.0 mg/kg) did not affect hot plate responses, whereas the 3.0 mg/kg oxycodone produced robust analgesia demonstrated with high response latencies. CBD alone did not produce increased response latencies. Furthermore, the subanalgesic and analgesic doses of oxycodone given in combination with CBD produced subadditive effects on hot plate latencies.

FIG. 3.

Effects of CBD and oxycodone on hot plate response latencies. Values represent the mean latency (seconds) of a hind-paw lick or flutter. A one-way ANOVA with Fisher's LSD post hoc analysis was used to analyze these data. *Significant difference from the saline group. ^†Significant difference from 8.0 mg/kg CBD. Sample sizes were n=10.

Consistent with these observations, a two-way ANOVA performed on these data revealed a significant main effects for oxycodone (F(2, 54)=20.066, p<0.001 and CBD, F(1, 54)=6.378, p=0.015), as well as a significant CBD×oxycodone interaction (F(2, 76)=15.654, p<0.001). To determine which oxycodone dose produced analgesia, a one-way ANOVA was performed on these data and revealed a significant main effect for oxycodone (F(2, 27)=33.070, p<0.001). Fisher's LSD postanalysis of the vehicle groups were conducted and revealed 3.0 mg/kg oxycodone produced significantly higher hot plate response latencies than saline (p<0.001), whereas 1.0 mg/kg oxycodone (p=0.086) was not significantly different than saline.

To determine if 7.5 mg/kg CBD produced antinociception, a one-way ANOVA of the saline groups was performed and revealed 7.5 mg/kg CBD alone did not produce significantly different response latencies compared with the vehicle group (F(1, 18)=1.500, p=0.236).

To determine whether CBD enhanced oxycodone analgesia, a one-way ANOVA was performed on the CBD groups and failed to reveal a significant main effect for CBD (F(2, 27), p=0.052). Planned comparisons revealed 7.5 mg/kg CBD +1.0 mg/kg oxycodone latencies had significantly lower response latencies compared with 7.5 mg/kg CBD (p=0.019). There was no significant difference between 7.5 mg/kg CBD and 7.5 mg/kg CBD +3.0 mg/kg oxycodone (p=0.478).

The effects of oxycodone on CBD-val-HS on hot plate responses are given in Figure 4. Vehicle and the subanalgesic dose of oxycodone (1.0 mg/kg) did not affect hot plate responses, whereas the 3.0 mg/kg oxycodone produced robust analgesia demonstrated with high response latencies. CBD-val-HS alone produced increased response latencies. Furthermore, the subanalgesic and analgesic doses of oxycodone given in combination with CBD-val-HS produced subadditive effects on hot plate latencies.

FIG. 4.

Effects of CBD-val-HS and oxycodone on hot plate response latencies. Values represent the mean latency (seconds) of a hind-paw lick or flutter. A one-way ANOVA with Fisher's LSD post hoc analysis was used to analyze these data. *Significant difference from the saline group. ^†Significant difference from 8.0 mg/kg CBD-val-HS. Sample sizes were n=9–17.

Consistent with these observations, a two-way ANOVA performed on these data revealed a significant main effect for oxycodone (F(2, 76)=3.830, p=0.026) and a significant CBD-val-HS×oxycodone interaction (F(2, 76)=5.761, p=0.005). The CBD-val-HS term was not significant (F(1, 76)=0.49, p=0.619). To determine which oxycodone dose produced analgesia, a one-way ANOVA was performed on the vehicle groups and revealed a significant main effect for oxycodone (F(2, 40)=6.477, p=0.004). Fisher's LSD post hoc analysis on the vehicle groups was conducted and revealed 1.0 mg/kg oxycodone was not significantly than saline (p=0.558), whereas 3.0 mg/kg oxycodone produced significantly higher hot plate response latencies than saline (p=0.001).

To determine if 8.0 mg/kg CBD-val-HS produced anti-nociception, a one-way ANOVA on the saline groups was performed and revealed 8.0 mg/kg CBD-val-HS produced significantly higher hot plate response latencies compared with the saline group (F(1, 35)=6.273, p=0.017).

To determine whether CBD-val-HS enhanced oxycodone analgesia, a one-way ANOVA was performed on the CBD-val-HS groups and revealed a significant main effect for CBD-val-HS (F(2, 36)=3.674, p=0.035). Fisher's LSD post hoc analysis revealed 8.0 mg/kg CBD-val-HS +1.0 mg/kg oxycodone produced a significantly lower hot plate response latency than 8.0 mg/kg CBD-val-HS (p=0.010). There was no significant difference between 8.0 mg/kg CBD-val-HS and 8.0 mg/kg CBD-val-HS +3.0 mg/kg oxycodone (p=0.230).

Abdominal writhing

The effects of oxycodone and CBD on abdominal writhing responses are given in Figure 5. Oxycodone produced a dose-dependent decrease in writhing response indicative of analgesia. In the saline-treated groups, CBD did not attenuate abdominal writhing. CBD in combination with a high dose of oxycodone appears to produce additive effects in attenuating abdominal writhes.

FIG. 5.

Effects of CBD and oxycodone in the abdominal writhing test. Values represent the mean number of writhes following an intraperitoneal injection of 0.7% acetic acid over a 30-min test session. Data were transformed using log square root and analyzed using a one-way ANOVA and Fisher's LSD post hoc analysis. *Significant difference from the saline group. ^†Significant difference from 8.0 mg/kg CBD. Sample sizes were n=5–10.

A two-way ANOVA was carried out, and as Levene's test for equality of variances was significant, data were transformed using log square root. This analysis revealed a significant main effect for oxycodone (F(2, 49)=26.271, p<0.001) but no significant main effect for CBD (F(1, 49)=1.222, p=0.274). The CBD×oxycodone interaction term was significant (F(2, 49)=0.106, p=0.043). To determine which oxycodone dose decreased abdominal writhes, a one-way ANOVA on the vehicle groups was conducted and revealed a significant main effect for oxycodone (F(2, 27)=48.037, p<0.001). Fisher's LSD post hoc analyses among these groups revealed 1.0 mg/kg oxycodone was not significantly different than saline (p=0.803), whereas 3.0 mg/kg oxycodone produced significantly lower abdominal writhes compared with saline (p<0.001).

To test whether CBD alone decreased writhing, a one-way ANOVA among the saline group was conducted and revealed 7.5 mg/kg CBD was not significantly different than saline (F(1, 18)=0.031, p=0.863).

To determine whether CBD enhanced oxycodone analgesia, a one-way ANOVA on the CBD groups was conducted and revealed a significant effect for CBD (F(2, 22)=5.128, p=0.015). Fisher's LSD post hoc analysis among these groups demonstrated 3.0 mg/kg oxycodone +8.0 mg/kg CBD significantly decreased abdominal writhing (p=0.005), whereas 1.0 mg/kg oxycodone +8.0 mg/kg CBD did not decrease abdominal writhing (p=0.138).

The effects of oxycodone and CBD-val-HS on abdominal writhing responses are given in Figure 6. Oxycodone produced a dose-dependent decrease in writhing response indicative of analgesia. In the saline-treated groups, CBD-val-HS also attenuated writhing illustrating this CBD analog possesses analgesic properties against inflammatory nociception. CBD-val-HS in combination with increasing doses of oxycodone appears to produce additive effects in attenuating abdominal writhes.

FIG. 6.

Effects of CBD-val-HS and oxycodone in the abdominal writhing test. Values represent the mean number of writhes following an intraperitoneal injection of 0.7% acetic acid over a 30-min test session. Data were transformed using log square root and analyzed using a one-way ANOVA and Fisher's LSD post hoc analysis. *Significant difference from the saline group. ^†Significant difference from 8.0 mg/kg CBD-val-HS. Sample sizes were n=8–13.

To determine which oxycodone dose decreased abdominal writhes, a one-way ANOVA of the vehicle groups were conducted and revealed a significant main effect for oxycodone, (F(2, 25)=23.209, p<0.001). Fisher's LSD post hoc analyses among the oxycodone groups found 1.0 mg/kg oxycodone was not significantly different compared with saline (p=0.322), whereas 3.0 mg/kg oxycodone produced significantly lower abdominal writhes than saline (p<0.001).

To test whether CBD-val-HS alone produced decreased writhing, a one-way ANOVA among the saline groups was conducted and revealed 8.0 mg/kg CBD-val-HS significantly lowered abdominal writhing compared with saline (F(1, 19)=5.978, p=0.024).

To determine whether CBD-val-HS enhanced oxycodone analgesia, a one-way ANOVA on the CBD-val-HS groups were conducted and revealed a significant effect for CBD-val-HS (F(2, 27)=32.032, p<0.001). Fisher's post hoc analysis among these groups demonstrated 1.0 mg/kg oxycodone +8.0 mg/kg CBD-val-HS did not decrease abdominal writhing compared with 8.0 mg/kg CBD-val-HS (p=0.098), whereas 3.0 mg/kg oxycodone +8.0 mg/kg CBD-val-HS significantly decreased abdominal writhing compared with 8.0 mg/kg CBD-val-HS (p<0.001).

Discussion

This study sought to determine whether CBD or a CBD derivative could (1) alter the development of oxycodone reward and (2) produce antinociception as stand-alone compounds and/or affect the antinociceptive properties of oxycodone against thermal and chemo-inflammatory nociceptive tests.

In the CPP paradigm, CBD-val-HS was void of rewarding or aversive properties and attenuated the rewarding effects of oxycodone place preference with a dose of 8.0 mg/kg. CBD produced condition place aversion at the highest dose tested (10.0 mg/kg) and did not attenuate the rewarding effects of oxycodone at any dose. A growing body of research has demonstrated the endocannabinoid system may play a significant role in opioid reward. CBD has shown the ability to block the effects of morphine reward in an ICSS paradigm and in the CPP paradigm.^20,21,24

Although our research has demonstrated CBD could not block the oxycodone reward, this may be owing to the more robust effect of oxycodone in comparison with morphine. It has been shown oxycodone's analgesic and rewarding properties are greater compared with morphine.^28–30 To our knowledge, this the first attempt to evaluate the ability of CBD to block the rewarding effects of oxycodone.

In the acute pain assays, CBD-val-HS administered alone produced analgesic effects in both assays, whereas CBD did not. Of interest, when administered in combination with subanalgesic and analgesic doses of oxycodone, there was a differential interaction across the two nociceptive assays. CBD and CBD-val-HS combined with subanalgesic dose of oxycodone produced subadditive responses in the hot plate assay but not in the abdominal writhing assay.

Data from the hot plate assay are consistent with Neelakantan et al., who demonstrated CBD in combination with morphine produce subadditive effects.²⁷ Unlike CBD, CBD-val-HS alone produced antinociceptive effects equivalent to an analgesic dose of 3.0 mg/kg oxycodone. Our laboratory has evaluated the pharmacokinetic (PK) profile on CBD-val-HS and CBD. Data from these studies revealed CBD-val-HS produced significantly higher drug load in various organs (liver, kidney, and spleen) and in plasma concentrations when compared with CBD.¹⁹ Of interest, this compound was shown to cross the blood–brain barrier, a significant finding in the use of this compound for the treatment of CNS-based disease conditions.¹⁹

Collectively, these studies illustrated CBD-val-HS has a superior absorption and a longer half-life compared with CBD.¹⁹ We hypothesize this PK profile provides greater antinociceptive effects demonstrated in the current studies compared with CBD is owing to a superior absorption profile, allowing binding to pain regulating sites. Studies to further ascertain this are ongoing in this laboratory.

An important finding from this research was CBD-val-HS alone possesses significant analgesic properties against acute thermal and chemo-inflammatory nociception. This work aligns well with earlier work from this laboratory that shows CBD-val-HS possesses analgesic activity in a murine model of chemotherapy-induced neuropathy and was as efficacious as oxycodone.¹⁸ Collectively, these studies suggest it may be unnecessary to rely on a dual CBD-val-HS and opioid formulation to treat certain pain conditions.

An important unanswered question is whether CBD-val-HS possesses analgesic activity across a broad range of other pain conditions including, among others, arthritic, cancer, and migraine models. It may be necessary to perform isobolograms across a broad range of opioids with this novel CBD derivative to create a set of novel formulations tailored to treating a wide variety of chronic pain conditions. Further pharmacodynamic and PK (PK/PD) studies correlated to these analgesic effects are needed to further characterize this analog. These experiments are currently underway in our laboratory and with collaborators.

Although the current studies used only male mice, it is important to evaluate these analgesic effects in female mice as studies show pain differences across sexes. A wealth of literature has demonstrated women have shown to be more sensitive to the behavioral and physiological effects of cannabinoids compared with men.³¹ We hypothesize the female mice will demonstrate a greater analgesic response and enhanced interaction with opioids compared with males. It is unknown what sex differences would reveal under measures of abuse-liability across sexes. We acknowledge that this is a significant limitation in this study and have ongoing studies in this laboratory to evaluate these differences.

As with any novel therapeutic, its use may be limited by adverse side effects. Future research should evaluate the side effects profile of CBD-val-HS formulation with opioids. Although the current research demonstrates the most serious issues of opioid addiction is mitigated by CBD-val-HS, it will be important to test this formulation for sedation, ataxia, respiratory depression, and other physiological side effects. It is unlikely that CBD-val-HS, as a stand-alone analgesic, will possess such characteristics as its parent molecule CBD does not.

Conclusion

Much of today's opioid epidemic is attributed to overuse of prescription opioids in pain management and CBD-val-HS may also show efficacy here as an abuse deterrent in a dual drug formulation. These data demonstrate CBD-val-HS alone or in an opioid formulation can interfere with reward processes, while retaining analgesia, represent a significant turning point in the opioid abuse crisis today.

Footnotes

Acknowledgments

The authors acknowledge Jontae D. Warren, SolEllena G. Cordova, and Jessica A. Cucinello-Ragland for their assistance in data collection. This research was submitted by the first author to the University of Mississippi in partial fulfillment to the requirement of the PhD degree.

Author Disclosure Statement

K.J.S., W.G., M. A.E., and H.M.H. are inventors on a patent filed for CBD-val-HS. Mahmoud ElSohly served as an unpaid consultant on the Advisory Board of Emerald Biosciences Inc., Costa Mesa, CA, USA.

Funding Information

Funding was provided by Emerald Biosciences Inc., Costa Mesa, CA, USA and the University of Mississippi's Center of Biomedical Research Excellence in Natural Products Neuroscience (P30GM122733).

Supplementary Material

Abbreviations Used

References

, Zhang

. Emerging drug targets for pain treatment. Eur J Pharmacol. 2012; 681:1–5.

Boer

, Detriche

, Forget

. Opioid-related side effects: postoperative ileus, urinary retention, nausea and vomiting, and shivering. A review of the literature. Best Pract Res Clin Anaesthesiol. 2017; 31:499–504.

Imam

, Kuo

, Ghassabian

, et al. Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression. NEPHBW. 2018; 131:238–255.

Kalso

, Edwards

, Moore

, et al. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004; 112:372–380.

Center for Behavioral Health Statistics and Quality (CBHSQ). 2017 National Survey on Drug Use and Health: Detailed Tables. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2018.

CDC/NCHS, National Vital Statistics

System

, Mortality. CDC WONDER. Atlanta, GA: US Department of Health and Human Services, CDC, 2018.

Moorman-Li

, Motycka

, Inge

, et al. A review of abuse-deterrent opioids for chronic nonmalignant pain. P T. 2012; 37:412–418.

Katz

. Abuse-deterrent opioid formulations: are they a pipe dream?. Curr Rheumatol Rep. 2008; 10:11–18.

Townsend

, Naylor

, Negus

, et al. Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats. Psychopharmacology (Berl). 2017; 234:2597–2605.

10.

Harris

, Gul

, ElSohly

, et al. Cannabinoid modulation of cisplatin induced neuropathy in mice. Planta Med. 2016; 82:1169–1182.

11.

Chiou

, Hu

, Ho

. Targeting the cannabinoid system for pain relief?. Acta Anaesthesiol Taiwan. 2013; 51:161–170.

12.

. An archaeological and historical account of cannabis in China. Econ Bot. 1974; 28:7–448.

13.

Meng

, Deshpande

. Cannabinoids in chronic non-cancer pain medicine: moving from the bench to the bedside. BJA Educ. 2020; 20:305–311.

14.

Fiz

, Duran

, Capella

, et al. Cannabis use in patients with fibromyalgia; effect on symptoms relief and health-related quality of life. PLoS One. 2011; 6:e18440.

15.

Whiting

, Wolff

, Deshpande

. Cannabinoids for medical use: a systemic review and meta-analysis. JAMA. 2015; 313:2456–2473.

16.

Walker

, Strangman

, Huang

. Cannabinoids and pain. Pain Res Manag. 2001; 6:74–79.

17.

Huestis

. Pharmacokinetics and metabolism of the plant cannabinoids, delta9-tetrahydrocannabinol, cannabidiol and cannabinol. Handb Exp Pharmacol. 2005:657–690.

18.

Harris

, Gul

, ElSohly

, et al. 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. Medical Cannabis. 2018; 1:54–59.

19.

Elsohly

, Majumdar

, Gul

, et al. Patent analyzing system. US10709681 B2, United States Patent and Trademark Office. 2017.

20.

Parker

, Burton

, Sorge

, et al. Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology (Berl). 2004; 175:360–366.

21.

Katsidoni

, Anagnostou

, Panagis

. Cannabidiol inhibits the reward- facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus. Addict Biol. 2013; 18:286–296.

22.

Lapririe

, Bagher

, Kelly

MEM

, et al. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015; 172:4790–4805.

23.

Kathmann

, Flau

, Redmer

, et al. Cannabidiol is an allosteric modulator at mu-and delta-opioid receptors. N Schmied Arch Pharmacol. 2005; 372:354–361.

24.

Markos

, Harris

, Gul

, et al. Effects of cannabidiol on morphine conditioned place preference in mice. Planta Med. 2018; 84:221–224.

25.

Tzschentke

. Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol. 2007; 12:227–462.

26.

Deuis

, Dvorakova

, Vetter

. Methods used to evaluate pain behaviors in rodents. Front Mol Neurosci. 2017; 10:284.

27.

Neelakantan

, Tallarida

, Reichenbach

, et al. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice. Behav Pharmacol. 2015; 26:304–314.

28.

Olesen

, Staahl

, Arendt-Nielsen

, et al. Different effects of morphine and oxycodone in experimentally evoked hyperalgesia: a human translational study. Br J Clin Pharmacol. 2010; 70:189–200.

29.

Nielsen

, Ross

, Lotfipour

, et al. Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain. 2007; 132:289–300.

30.

Morgan

, Christie

. Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human. Br J Pharmacol. 2011; 164:1322–1334.

31.

Craft

, Marusich

, Wiley

. Sex differences in cannabinoid pharmacology: a reflection of differences in the endocannabinoid system?. Life Sci. 2013; 92:476–481.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.15 MB