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
Hannah Marie Harris, Waseem Gul, Mahmoud A. ElSohly, Kenneth J. Sufka
Medical Cannabis and Cannabinoids, 2018, 1, 54–59
Preclinical Science and Clinical Studies – Research Article
Objective : This research examined whether a cannabidiol (CBD)-opioid pharmacotherapy could attenuate cisplatin-induced tactile allodynia.
Methods : Mice (C57BL/6) were given 6 doses of 2.3 mg/kg cisplatin intraperitoneally (IP) on alternating days to induce tactile allodynia as quantified using an electric von Frey (eVF). Test groups in Experiment 1 received either vehicle, 0.1 or 2.5 mg/kg morphine, 1.0 or 2.0 CBD, or the 2 drugs in combination. Test groups in Experiment 2 received either vehicle, 0.1 or 2.5 mg/kg morphine, 1.0, 2.0, 3.0, or 4.0 mg/kg NB2111 (a long-acting CBD analogue), or the 2 drugs in combination. Drugs were administered IP 45 min before eVF assessment.
Results : Cisplatin produced tactile allodynia that was attenuated by 2.5 mg/kg morphine. Both CBD and NB2111 produced dose-dependent attenuation of tactile allodynia. CBD and NB2111, given in combination with sub-analgesic doses of morphine, produced attenuation of tactile allodynia equivalent to 2.5 mg/ kg morphine. Conclusions: While both CBD and NB2111, either alone or in combination with sub-analgesic doses of opioids, exhibited analgesic effects, NB2111 could be capable of superior analgesia over time by virtue of enhanced pharmacokinetics.
Keywords : Cisplatin · Cannabidiol · Cisplatin · Neuropathy · Analgesia · Allodynia
Cisplatin is a common agent in chemotherapy used to treat a variety of cancers. Unfortunately, cisplatin has a dose-limiting effect, wherein 50–85% of all patients develop peripheral neuropathy 3–6 months into treatment. Cisplatin-induced neuropathy (CIN) presents in a “stocking and glove” distribution causing tingling paresthesia, numbness, and allodynia [1, 2]. Pain management for CIN includes anticonvulsant, antidepressant, and nonsteroidal anti-inflammatory drugs. These drugs prove to be well tolerated in patients but show little efficacy in treating CIN [2–4]. While opioids can provide effective CIN pain relief, 76–96% of all patients report aversive side effects that include sedation, nausea, and fatigue which limit usefulness and diminish patients’ quality of life [5, 6]. Added concerns of opioid therapy include tolerance, dose escalation, and dependence that can lead to withdrawal symptoms upon CIN resolution . Collectively, these observations suggest a need to develop novel pharmacotherapies
Cannabinoids (CB) are used in oncology settings to control nausea, weight loss, lack of appetite, and chemotherapy- related pain . CB analgesia in both chronic and acute pain models is mediated through CB1 and CB2 receptors that are differentially expressed in the central and peripheral nervous systems [9, 10]. An emerging body of literature supports the notion that endocannabinoid systems may also modulate CIN. For example, CB1 and CB2 direct and indirect agonists attenuate tactile allodynia in rodent models of CIN [5, 11, 12]. However, like non-opioid therapies, CB compounds have modest efficacy and are of limited usefulness.
CB1 and opioid receptors are co-localized in pain pathways. Evidence suggests that a dual pharmacotherapy at these targets may increase CB-mediated analgesic effects [13–16]. For example, the CB1 agonist THC shows synergistic effects with sub-analgesic doses of the μ-opioid agonist morphine in a rat arthritic pain model . However, the use of any CB1 agonist in oncology settings is unlikely due to these compounds increasing the proliferation and growth of some tumor cells . 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 . Whether a combined CBD-opioid or a bioengineered synthetic analogue of CBD-opioid pharmacotherapy could provide highly efficacious pain relief against CIN is unknown. In Experiment 1, we hypothesize a CBD-opioid interaction may enhance the analgesic effects against CIN allodynia. Further, in Experiment 2, we hypothesize a bio-engineered CBD-opioid pharmacotherapy could also produce robust analgesic effects compared to CBD alone and in combination with an opioid.