Introduction
!Pain is a common complaint in oncology patients and can diminish their quality of life [1,2]. Cisplatin is a common and effective chemotherapeutic against a variety of tumors. However, it has a dose-limiting effect, where 40-80 % of patients develop neuropathic pain 3-6 months into treatment [3]. Moreover, CIN does not abate upon discontinuation of treatment, a phenomenon known as "coasting" [4]. A large meta-analysis revealed that CIN was prevalent in 68 %, 60%, and 30 % of patients one, three, and greater than six months after cisplatin discontinuation, respectively [5]. Several approaches to prevent CIN have yielded disappointing results, as these compounds also interfere with cisplatinʼs antitumor properties [6,7]. Current treatment for CIN includes nortriptyline, gabapentin, and lamotrigine. Each of these have shown efficacy against other neuropathic pain syndromes, but show little efficacy in CIN [8]. Collectively, these observations suggest a need to identify novel targets for the treatment of CIN. Targeting the cannabinoid system has shown efficacy in a variety of clinical syndromes including pain. Synthetic cannabinoids produce analgesia in a number of nociceptive assays and these effects can be produced by targeting either CB1 and/or CB2 receptors [9][10][11]. There is also recent evidence that CB targets may be efficacious in treating CIN. For example, selective CB1 and CB2 receptor agonists, as well as compounds that increase endocannabinoid tone, attenuate tactile allodynia in rodent models of CIN [12][13][14].Abstract ! Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy.
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