The periaqueductal gray contributes to bidirectional enhancement of antinociception between morphine and cannabinoids

Co-administration of opioids and cannabinoids can enhance pain relief even when administered on different days. Repeated systemic administration of morphine has been shown to enhance the antinociceptive effect of tetrahydrocannabinol (THC) administered 12h later, and repeated microinjection of the cannabinoid receptor agonist HU-210 into the ventrolateral periaqueductal gray (PAG) has been shown to enhance the antinociceptive effect of morphine administered 1day later. The primary objective of the present study was to test the hypothesis that this cannabinoid/opioid interaction is bidirectional. Experiment 1 showed that microinjection of morphine into the ventrolateral PAG of male Sprague–Dawley rats twice daily for 2days enhanced the antinociceptive effect of HU-210 measured 1day later. In Experiment 2, twice daily systemic injections of THC enhanced the antinociceptive effect of morphine administered 1day later. These results complement the previously mentioned studies by showing that morphine and cannabinoid interactions are bidirectional and that the ventrolateral PAG plays an important role in this effect. In contrast to the PAG, repeated administration of HU-210 or the cannabinoid receptor agonist, WIN 55,212-2, into the RVM had a neurotoxic effect. Rats became ill following repeated cannabinoid administration whether given alone or with morphine. Presumably, this neurotoxic effect was caused by the high cannabinoid concentration following RVM microinjection because rats did not become ill following repeated systemic THC administration. These findings indicate that alternating opioid and cannabinoid treatment could produce a longer lasting and more potent analgesia than either compound given alone. ► PAG mediated cannabinoid antinociception is enhanced in morphine tolerant rats. ► Systemic morphine antinociception is enhanced following repeated THC administration. ► Repeated microinjection of cannabinoids into the RVM is neurotoxic. ► The enhanced antinociception from opioid/cannabinoid interactions is bidirectional

High-CBD Cannabis Vapor Attenuates Opioid Reward and Partially Modulates Nociception in Female Rats

Chronic pain patients report analgesic effects when using cannabidiol (CBD), a phytocannabinoid found in whole-plant cannabis extract (WPE). Several studies suggest that cannabis-derived products may serve as an analgesic adjunct or alternative to opioids, and importantly, CBD may also attenuate the abuse potential of opioids. Vaping is a popular route of administration among people who use cannabis, however both the therapeutic and hazardous effects of vaping are poorly characterized. Despite the fact that chronic pain is more prevalent in women, the ability of inhaled high-CBD WPE to relieve pain and reduce opioid reward has not been studied in females. Here, we present a comprehensive analysis of high-CBD WPE vapor inhalation in female rats. We found that WPE was modestly efficacious in reversing neuropathy-induced cold allodynia in rats with spared nerve injury (SNI). Chronic exposure to WPE did not affect lung cytoarchitecture or estrous cycle, and it did not induce cognitive impairment, social withdrawal or anxiolytic effects. WPE inhalation prevented morphine-induced conditioned place preference and reinstatement. Similarly, WPE exposure reduced fentanyl self-administration in rats with and without neuropathic pain. We also found that WPE vapor lacks of reinforcing effects compared to the standard excipient used in most vapor administration research. Combined, these results suggest that although high-CBD vapor has modest analgesic effects, it has a robust safety profile, no abuse potential, and it significantly reduces opioid reward in females. Clinical studies examining high-CBD WPE as an adjunct treatment during opioid use disorder are highly warranted

Perceived Efficacy, Reduced Prescription Drug Use, and Minimal Side Effects of Cannabis in Patients with Chronic Orthopedic Pain

Introduction: Although cannabis is widely used for the treatment of chronic pain, most research relies on patient self-report and few studies have objectively quantified its efficacy and side effects. Extant inventories for measuring cannabis use were not designed to capture the medically relevant features of cannabis use, but rather were designed to detect problematic use or cannabis use disorder. Thus, we sought to capture the medically relevant features of cannabis use in a population of patients with orthopedic pain and pair these data with objective measures of pain and prescription drug use. Materials and Methods: In this prospective observational study, orthopedic pain patients were enrolled in Pennsylvania\u27s medical cannabis program by their treating pain management physician, received cannabis education from their physician at the time of certification, and purchased products from state-licensed cannabis retailers. Results: Medical cannabis use was associated with clinical improvements in pain, function, and quality of life with reductions in prescription drug use; 73% either ceased or decreased opioid consumption and 31% discontinued benzodiazepines. Importantly, 52% of patients did not experience intoxication as a side effect of cannabis therapy. Significant clinical benefits of cannabis occurred within 3 months of initiating cannabis therapy and plateaued at the subsequent follow-ups. Conclusions: This work provides a direct relationship between the initiation of cannabis therapy and objectively fewer opioid and benzodiazepine prescriptions. Our work also identifies specific subpopulations of patients for whom cannabis may be most efficacious in reducing opioid consumption, and it highlights the importance of both physician involvement and patient self-titration in symptom management with cannabis

The Nose Knows: Aroma, but Not THC Mediates the Subjective Effects of Smoked and Vaporized Cannabis Flower

Previous studies have shown that cannabis consumers are willing to pay more money for higher-quality products; however, the definition of “quality” cannabis has not been defined. Despite the known health risks of THC overuse, THC potency has been adopted as the primary market-driving feature of cannabis products. The purpose of this study was to objectively identify features of cannabis that contribute to its appealing subjective effects. In the course of conducting cannabis competitions, commercially available cannabis inflorescences were distributed to healthy volunteers (“judges”) in a randomized, double-blind fashion. Anonymous online survey data about the subjective effects of each cannabis sample were analyzed independently, by researchers not involved with the competitions. Pleasant subjective aroma (but not terpene expression, THC potency, or THC dose) was positively correlated with pleasant subjective effects. There was also a moderate but significant negative association between the amount of cannabis consumed and subjective appeal. These results suggest that, unlike THC potency, pleasant aroma is predictive of pleasant subjective effects. Similar to other agricultural commodities such as coffee and tea, aroma appears to be a robust indicator of the quality of cannabis inflorescence. These findings have wide-reaching public health implications, given the well-established health risks of THC overuse

Effects of inflammatory pain on CB1 receptor in the midbrain periaqueductal gray.

IntroductionThe periaqueductal gray (PAG) mediates the antinociceptive properties of analgesics, including opioids and cannabinoids. Administration of either opioids or cannabinoids into the PAG induces antinociception. However, most studies characterizing the antinociceptive properties of cannabinoids in the PAG have been conducted in naive animals. Few studies have reported on the role of CB1 receptors in the PAG during conditions which would prompt the administration of analgesics, namely, during pain states.ObjectivesTo examine inflammatory pain-induced changes in CB1 receptor expression and function in the midbrain periaqueductal gray.MethodsIn this study, we used the Complete Freund Adjuvant model to characterize CB1 receptor expression and G-protein coupling during persistent inflammatory pain.ResultsInflammatory pain induced an upregulation in the expression of synaptic CB1 receptors in the PAG. Despite this pain-induced change in CB1 expression, there was no corresponding upregulation of CB1 mRNA after the induction of inflammatory pain, suggesting a pain-induced recruitment of CB1 receptors to the synaptic sites within PAG neurons or increased coupling efficiency between the receptor and effector systems. Inflammatory pain also enhanced ventrolateral PAG CB1 receptor activity, as there was an increase in CP55,940-stimulated G-protein activation compared with pain-naïve control animals.ConclusionThese findings complement a growing body of evidence which demonstrate pain-induced changes in brain regions that are responsible for both the analgesic and rewarding properties of analgesic pharmacotherapies. Because much of our understanding of the pharmacology of cannabinoids is based on studies which use largely pain-naïve male animals, this work fills in important gaps in the knowledge base by incorporating pain-induced adaptations and cannabinoid pharmacology in females

Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors

Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functional changes induced by inflammatory pain on MOR-mediated mesolimbic DA transmission and on rat intravenous heroin self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. In the presence of inflammatory pain, heroin intake under an FR schedule was increased for high, but attenuated for low, heroin doses with concomitant alterations in mesolimbic MOR function suggested by DA microdialysis. Consistent with the reduction in low dose FR heroin self-administration, inflammatory pain reduced motivation for a low dose of heroin, as measured by responding under a PR schedule of reinforcement, an effect dissociable from high heroin dose PR responding. Together, these results identify a connection between inflammatory pain and loss of MOR function in the mesolimbic dopaminergic pathway that increases intake of high doses of heroin. These findings suggest that pain-induced loss of MOR function in the mesolimbic pathway may promote opioid dose escalation and contribute to opioid abuse-associated phenotypes. This study provides critical new insights that show that inflammatory pain alters heroin intake through a desensitization of MORs located within the VTA. These findings expand our knowledge of the interactions between inflammatory pain and opioid abuse liability, and should help to facilitate the development of novel and safer opioid-based strategies for treating chronic pain

Pain-Induced Negative Affect Is Mediated via Recruitment of The Nucleus Accumbens Kappa Opioid System.

Negative affective states affect quality of life for patients suffering from pain. These maladaptive emotional states can lead to involuntary opioid overdose and many neuropsychiatric comorbidities. Uncovering the mechanisms responsible for pain-induced negative affect is critical in addressing these comorbid outcomes. The nucleus accumbens (NAc) shell, which integrates the aversive and rewarding valence of stimuli, exhibits plastic adaptations in the presence of pain. In discrete regions of the NAc, activation of the kappa opioid receptor (KOR) decreases the reinforcing properties of rewards and induces aversive behaviors. Using complementary techniques, we report that in vivo recruitment of NAc shell dynorphin neurons, acting through KOR, is necessary and sufficient to drive pain-induced negative affect. Taken together, our results provide evidence that pain-induced adaptations in the kappa opioid system within the NAc shell represent a functional target for therapeutic intervention that could circumvent pain-induced affective disorders. VIDEO ABSTRACT