Cannabis has been used for centuries for its medicinal properties. Given the dangerous and unpleasant side effects of existing analgesics, the chemical constituents of Cannabis have garnered significant interest for their antinociceptive, anti-inflammatory and neuroprotective effects. To date, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) remain the two most widely studied constituents of Cannabis in animals. These studies have led to formulations of THC and CBD for human use; however, chronic pain patients also use different strains of Cannabis (sativa, indica and ruderalis) to alleviate their pain. These strains contain major cannabinoids, such as THC and CBD, but they also contain a wide variety of cannabinoid and noncannabinoid constituents. Although the analgesic effects of Cannabis are attributed to major cannabinoids, evidence indicates other constituents such as minor cannabinoids, terpenes and flavonoids also produce antinociception against animal models of acute, inflammatory, neuropathic, muscle and orofacial pain. In some cases, these constituents produce antinociception that is equivalent or greater compared to that produced by traditional analgesics. Thus, a better understanding of the extent to which these constituents produce antinociception alone in animals is necessary. The purposes of this review are to (1) introduce the different minor cannabinoids, terpenes, and flavonoids found in Cannabis and (2) discuss evidence of their antinociceptive properties in animals.
Traditional pain‐evoked tests (e.g., hot plate and tail withdrawal tests) do not mimic the disruptive effects of pain on daily life, a primary outcome measure used for pain in humans. To solve this problem, we demonstrated that pain‐depressed home cage wheel running is an objective and clinically relevant measure of the functional consequences of chronic inflammatory pain in the rat. However, few studies have examined the functional consequences of acute pain; thus, the aim of this study was to examine the effects of acute formalin‐induced inflammatory pain on function as measured by home cage wheel running. Rats were housed in individual cages containing a computerized running wheel. Rats were allowed free access to the wheel 23 hours/day for 7 days prior to the induction of hindpaw inflammation to acquire stable running levels. Wheel running during the 23 hours immediately prior to induction of inflammation was used as the baseline. Inflammation was induced with an intraplantar injection of formalin (5%, 0.05 mL) into the right hindpaw. The functional effects of a single formalin injection were apparent as indicated by decreased wheel running after the first hour following injection. Interestingly, wheel running also decreased in the 7th hour following formalin injection. In the 7th hour, wheel running was depressed in the absence of mechanical allodynia and spontaneous pain behaviors, suggesting that pain‐evoked behaviors and decreased function are independent of each other. A pretreatment of the nonsteroidal anti‐inflammatory drug ketoprofen (10 mg/kg) prevented depression of wheel running in both the 1st and 7th hour. These results indicate that continuous monitoring of the functional consequences of pain using home cage wheel running reveal insights into long‐term changes in behavior resulting from acute pain, and that early treatment may prevent functional deficits due to acute pain.
Chronic pain affects over 1.5 billion people worldwide and decreases activity to diminish people's quality‐of‐life. Traditional opioids (e.g., morphine) are the gold standards for treating pain, yet their use is limited by side effects including constipation, addiction, and death. New pain treatments are desperately needed, yet drug development for pain has failed for many reasons. The first reason is that pain in laboratory animals has not been assessed in the same way pain is assessed in humans. This results in a failure of translating drugs from the lab into effective treatments in the clinic. The second reason is that new drugs with novel mechanisms of action have not been identified. To solve the first problem, we used running wheels to continuously monitor activity of rats in order to understand the effects of pain and analgesia on daily activity ‐ which is the same way physicians diagnose and manage pain in humans. We found that induction of inflammatory pain depresses wheel running just as pain decreases activity in humans. To solve the second problem, we tested a peripherally‐restricted opioid, loperamide, that does not enter the brain or spinal cord eliminating the possibility of addiction or respiratory suppression. Loperamide activates opioid receptors in the peripheral nervous system. We hypothesized that loperamide will provide pain relief without side effects. Twenty‐four hours after inducting inflammatory pain, rats were injected with either 1, 3, or 5 mg/kg of loperamide. 1 mg/kg loperamide restored wheel running immediately after injection; however, the 3 mg/kg and 5 mg/kg doses depressed running in all rats. Thus, low doses of loperamide produce pain relief and restore wheel running activity after inflammatory pain in rats, but high doses impair activity. In conclusion, low loperamide doses may be a novel way to treat pain and restore activity without side effects in human and veterinary medicine.
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