The following is Part 1 of a three-part series of selected talks from the 2015 annual meeting of the Society for Neuroscience, held October 17-21, 2015, in Chicago, Illinois, US. Also see Part 2 and Part 3.
Whether cannabis can effectively and safely alleviate pain remains a matter of debate, but preclinical studies, patient anecdotes, and small clinical trials all point to their promising potential (see PRF related news). One thing everyone agrees on: More research is needed to understand the basic science underlying the effects of cannabinoids on pain processing. Several poster presentations at the 2015 annual meeting of the Society for Neuroscience investigated the effects of newly developed synthetic cannabinoids in animal models of neuropathic and inflammatory pain.
Cannabinoids are the active compounds found in the plant Cannabis sativa, also known as marijuana (and a host of other names). Whether derived from the plant or synthetically, cannabinoids exert their effects through an endogenous cannabinoid system, which plays many roles in the brain, including in pain modulation. The primary compound found in cannabis, tetrahydrocannabinol (THC), activates the cannabinoid receptor CB1 found on neurons, which gives rise to the drug’s psychoactive effects. The CB2 receptor, in contrast, is found on immune cells—both outside the central nervous system (CNS) and on CNS microglia. Activation of CB2 receptors is not thought to produce the psychoactive effects that limit the use of THC and other CB1 agonists in people.
Rebecca Craft and undergraduate student Nicholas Greene, Washington State University, Pullman, US, tested the effects of a synthetic cannabinoid that binds preferentially to CB2 receptors in rat models of acute and chronic inflammatory pain. Rats were injected in the hindpaw with complete Freund’s adjuvant (CFA), after which they developed mechanical allodynia and thermal hyperalgesia. Three days after injection, the researchers administered JWH015, a CB2-preferring synthetic cannabinoid, which significantly reduced rats’ mechanical and thermal hypersensitivity. Interestingly, the drug failed to alleviate mechanical allodynia and thermal hyperalgesia when given just two and a half hours after CFA injection. “We wondered, Could we get better pain relief if the drug was on board to begin with? But that didn’t work at all,” Craft said. The result is congruent with other findings that cannabinoids are more effective against chronic rather than acute pain states (Karst et al., 2010). “That also suggests that the immune effects of cannabinoids—which are apparently substantial—are more clinically significant in later phases of inflammation,” Craft said.
Male and female rats responded slightly differently to the drug treatment. “We saw a complete reversal of allodynia in females and only a partial reversal in males,” Craft told PRF. It was unclear whether the gender effect arose because the drug was less potent in males—in which case a higher dose could provide the full effect—or if the drug’s efficacy was lower in males, in which case no amount of drug would provide the same effect seen in females. Craft had previously reported similar findings regarding the sensitivity of rodents to THC, thought to reflect sex differences in the endocannabinoid system (Craft et al., 2013). “There are a few studies showing greater effects of cannabinoids in women than in men that make us think that there may be similar sex differences in the endocannabinoid system in humans as we are seeing in rodents,” Craft said.
Igor Spigelman, University of California, Los Angeles, US, hypothesized that the psychoactive side effects of CB1 receptor activation might be avoided by restricting a CB1 agonist to the periphery. Previous reports have shown the presence of CB1 receptors on the peripheral terminals of dorsal root ganglia (DRG) neurons of various sizes, as well as in peripheral immune cells and in keratinocytes (Spigelman, 2010). Together with chemist Herbert Seltzman, Research Triangle Institute, North Carolina, US, Spigelman developed synthetic, peripherally restricted CB1 agonists that reduced pain-related behaviors in rats in the sciatic nerve injury model of neuropathic pain, according to results they have previously presented but not published. This year, they tested a peripherally restricted compound in a rat model of chemotherapy-induced peripheral neuropathy (CIPN). “The side effects of chemotherapy are a major limiting factor in the successful treatment of many cancers, and the most severe side effect, which cannot be treated effectively, is painful neuropathy,” Spigelman told PRF. In the cisplatin model of CIPN, hindpaw injection of the peripherally restricted synthetic CB1 agonist PrNMI “completely suppressed mechanical and cold allodynia, which are the two main complaints of patients with CIPN,” Spigelman said.
The researchers confirmed that the drug’s anti-allodynic effects were mediated through CB1 receptors, because a CB1 receptor antagonist blocked the pain relief, but a CB2 antagonist had no effect. To demonstrate that the compound was indeed restricted to the periphery, the researchers treated healthy rats with the same dose of PrNMI used to reduce allodynia. The rats behaved normally on several tests of CNS or motor impairment, whereas performance was impaired in rats that received a centrally acting CB1 receptor agonist, as expected. Finally, the investigators gave cisplatin-treated rats PrNMI daily for two weeks. “That showed that, over 14 days of treatment, there was little development of tolerance, because treatment continued to be effective,” Spigelman said. The researchers also tested male and female rats separately: While male and female rats developed mechanical and cold allodynia at slightly different rates, they appeared similar at 30 days after cisplatin treatment, and PrNMI reversed allodynia fully in both sexes. In collaboration with Brian Schmidt, New York University, US, the researchers showed that PrNMI also alleviated mechanical allodynia in mouse models of tongue and paw cancer.
Together, the studies suggest that targeting cannabinoid receptors other than central CB1 could be an effective strategy to treat chronic neuropathic and inflammatory pain conditions.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.
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