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Chronic pain is the most common reason reported for using medical cannabis. The goal of this research was to determine if the two primary phytocannabinoids, THC and CBD, are effective treatments for persistent inflammatory pain. In Experiment 1, inflammation was induced in male and female rats by intraplantar injection of complete Freund's adjuvant (CFA). Then THC (0.0-4.0 mg/kg i.p.) or CBD (0.0-10 mg/kg i.p.) was administered twice-daily for 3 days. On day 4, vehicle, THC, or CBD was administered and allodynia, hyperalgesia, weight-bearing, locomotor activity, and hindpaw edema were assessed 0.5-4 h post-injection. In Experiment 2, CFA- or mineral oil (control)-treated rats were given vehicle, THC (2.0 mg/kg), or CBD (10 mg/kg) in the same manner as in Experiment 1. Four h post-injection on day 4, serum samples were taken for analysis of cytokines known to influence inflammatory pain: interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. THC dose-dependently reduced pain-related behaviors but did not reduce hindpaw edema, and little tolerance developed to THC's effects. In contrast, CBD effects on inflammatory pain were minimal. THC produced little-to-no change in serum cytokines, whereas CBD decreased IL-1β, IL-10, and IFN-γ, and increased IL-6. Few sex differences in antinociception or immune modulation were observed with either drug, but adjuvant-induced immune activation was greater in males than females. These results suggest that THC may be more beneficial than CBD for reducing inflammatory pain, in that THC maintains its efficacy with short-term treatment in both sexes, and does not induce immune activation. SIGNIFICANCE STATEMENT: CBDs and THCs pain-relieving effects are examined in male and female rats with persistent inflammatory pain to determine if individual phytocannabinoids could be a viable treatment for men and women with chronic inflammatory pain. Additionally, sex differences in the immune response to an adjuvant and to THC and CBD are characterized to provided preliminary insight into immune-related effects of cannabinoid-based therapy for pain.
Learn More >Neuropeptides play important modulatory roles throughout the nervous system, functioning as direct effectors or as interacting partners with other neuropeptide and neurotransmitter systems. Limbic brain areas involved in learning, memory and emotions are particularly rich in neuropeptides. This review will focus on the amygdala, a limbic region that plays a key role in emotional-affective behaviors and pain modulation. The amygdala is comprised of different nuclei; the basolateral (BLA) and central (CeA) nuclei and in between, the intercalated cells (ITC), have been linked to pain-related functions. A wide range of neuropeptides are found in the amygdala, particularly in the CeA, but this review will discuss those neuropeptides that have been explored for their role in pain modulation. Calcitonin gene-related peptide (CGRP) is a key peptide in the afferent nociceptive pathway from the parabrachial area and mediates excitatory drive of CeA neurons. CeA neurons containing corticotropin releasing factor (CRF) and/or somatostatin (SOM) are a source of long-range projections and serve major output functions, but CRF also acts locally to excite neurons in the CeA and BLA. Neuropeptide S (NPS) is associated with inhibitory ITC neurons that gate amygdala output. Oxytocin and vasopressin exert opposite (inhibitory and excitatory, respectively) effects on amygdala output. The opioid system of mu, delta and kappa receptors (MOR, DOR, KOR) and their peptide ligands (β-endorphin, enkephalin, dynorphin) have complex and partially opposing effects on amygdala function. Neuropeptides therefore serve as valuable targets to regulate amygdala function in pain conditions.
Learn More >Haloperidol is a neuroleptic drug with high affinity towards the σ receptor (σR), acting as antagonist that decreases neuropathic pain, but has CNS side effects. This work describes the design and synthesis of a novel analog N‑(1‑benzylpiperidin‑4-yl)‑4‑fluorobenzamide (LMH-2), which produced antihyperalgesic and antiallodynic effects in rats with neuropathy induced by chronic constriction injury of the sciatic nerve (CCI), being more active than gabapentin (The most widely used drug for the treatment of neuropathic pain).
Learn More >Contactin-associated protein-like 2 (CNTNAP2 or CASPR2) is a neuronal transmembrane protein of the neurexin superfamily that is involved in many neurological diseases, such as autism and pain hypersensitivity. We recently found that Cntnap2 mice showed elevated Akt-mTOR activity in the brain, and suppression of the Akt-mTOR pathway rescued the social deficit in Cntnap2 mice. In this study, we found that the dorsal root ganglion (DRG) from Cntnap2 mice also showed hyperactive Akt-mTOR signaling. Treatment with the Akt inhibitor LY94002 or the mTOR inhibitor rapamycin attenuated pain-related hypersensitivity to noxious mechanical stimuli, heat, and inflammatory substances. Further, suppression of mTOR signaling by rapamycin decreased DRG neuronal hyperexcitability. We further indicated that treatment with the FDA-approved drug metformin normalized the hyperactive Akt-mTOR signaling, and attenuated pain-related hypersensitivity in Cntnap2 mice. Our results thus identified hyperactive Akt-mTOR signaling pathway as a promising therapeutic target for pain-related hypersensitivity in patients with dysfunction of CNTNAP2.
Learn More >Mu opioid receptor (MOPr) agonists are thought to produce analgesia via modulation of G-protein-coupled intracellular signalling pathways whereas the β-arrestin2 pathway is proposed to mediate opioid-related adverse effects. Here, we report the antinociception, constipation and respiratory depressant profile of CYX-6, a potent MOPr agonist that is also a delta and a kappa opioid receptor (DOPr/KOPr) antagonist and that lacks β-arrestin2 recruitment at each of the MOPr, DOPr and the KOPr. In anaesthetised male Sprague Dawley rats, an intracerebroventricular (i.c.v.) guide cannula was stereotaxically implanted. After 5-7 days post-surgical recovery, rats received a single i.c.v. bolus dose of CYX-6 (3-30 nmol), morphine (100 nmol) or vehicle. Antinociception was assessed using the warm water tail flick test (52.5 ± 0.5 °C). Constipation was assessed using the charcoal meal gut motility test and the castor oil-induced diarrhoea test. Respiratory depression was measured by whole-body plethysmography in awake, freely moving animals, upon exposure to a hypercapnic gas mixture (8% CO, 21% O and 71% N). The intrinsic pharmacology of CYX-6 given by the i.c.v. route in rats showed that it produced dose-dependent antinociception. It also produced respiratory stimulation rather than depression and it had a minimal effect on intestinal motility in contrast to the positive control, morphine. CYX-6 is an endomorphin-2 analogue that dissociates antinociception from constipation and respiratory depression in rats. Our findings provide useful insight to inform the discovery and development of novel opioid analgesics with a superior tolerability profile compared with morphine.
Learn More >The TRPV1 ion channel is a neuronal sensor that plays an important role in nociception and neuropathic as well as inflammatory pain. In clinical trials, hyperthermia and thermo-hypoaesthesia turned out as major side effects of TRPV1 antagonists, preventing successful development of such molecules as analgesics. In vitro studies demonstrated that the TRPV1 ion channel is a polymodal sensor integrating stimuli from molecular modulators with temperature, pH and transmembrane potential. Temperature dependent gating is suggested to constitute the molecular basis for its role in heat sensation and body temperature regulation. Drug discovery scientists since many years seek to obtain "thermoneutral" TRPV1 inhibitors, blocking the channels sensitivity for painful stimuli while keeping its temperature mode of activation unaffected. Aiming for a screening rational for the identification of thermoneutral TRPV1 antagonists, we broadly characterized the prototypic small molecule TRPV1 inhibitors GRT12360V and GRTE16523. In vitro, GRT12360V demonstrated pan-modality inhibition on human, cynomolgus and rodent TRPV1, whereas GRTE16523 selectively bypassed the channels temperature mode on human and cynomolgus TRPV1 and revealed partial agonism on rodent channels. Strikingly, in vivo, GRT12360V induced hyperthermia in all species tested whereas GRTE16523 proved thermoneutral in cynomolgus monkeys and induced hypothermia in rodents. Hence, working out the different in vitro to in vivo correlations of two compounds, we suggest temperature dependent voltage gating as key parameter when screening for thermoneutral TRPV1 inhibitors. We highlight a species difference of molecular TRPV1 pharmacology between primates and rodents and provide a methodological breakthrough to engineer thermoneutral TRPV1 antagonists with improved therapeutic safety.
Learn More >The antihyperalgesic and sedative effects of the α2-subunit preferring GABA positive allosteric modulator (GAM), N-Desmethyl-Clobazam (NDMC), 20 and 60 mg, were assessed in a randomized, placebo and active-controlled (clonazepam 1,5 mg), 4-way crossover study, in healthy volunteers, using the UVB-induced experimental pain model. Single (20, 40, 60 mg) and repeated doses (20mg over 15 days) NDMC pharmacokinetic were evaluated. Thirty-two subjects participated to the study. Primary outcome parameter was maximal change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH). ASH decreased under all treatments. Mean (SD) relative change was 79 (22) %, 83 (24) %, 77 (30) % and 92 (16) % for placebo, NDMC20, NDMC60 and clonazepam, respectively. Neither absolute change nor relative change in ASH was significantly different between NDMC60 and placebo (mean difference= 2.3 cm [95%CI 4.0 to 8.5], p=0.462 and 0.4% [-11.9 to 12.6], p=0.952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference= 39 mm [30 to 49] on a visual analog scale, p<0.001) while NDMC was free of sedative effect. NDMC pharmacokinetic after single doses showed poor absorption, but was linear. Steady-state plasma concentrations of NDMC20 were attained within 14 days, with low between-subjects variability. Mean steady-state concentration (C , SD) reached 209 (22) ng/mL. NDMC absence of sedative effect and its overall well characterized safety coming from years of utilization as a metabolite from clobazam, raise the prospect of dose escalating trials in patients to quantify its clinical utility.
Learn More >Hyperalgesia is a heightened pain response to a noxious stimulus and is a hallmark of many common neuropathic and chronic pain conditions. In a double-blind placebo-controlled drug-crossover trial the effects of concomitant and delayed minocycline treatment on the initiation and resolution of muscle hyperalgesia were tested.
Learn More >The ventral tegmental area (VTA) is a major target of addictive drugs and receives multiple GABAergic projections originating outside the VTA. We describe differences in synaptic plasticity and behavior when optogenetically driving two opiate-sensitive GABAergic inputs to the VTA, the rostromedial tegmental nucleus (RMTg), and the periaqueductal gray (PAG). Activation of GABAergic RMTg terminals in the VTA in vivo is aversive, and low-frequency stimulation induces long-term depression in vitro. Low-frequency stimulation of PAG afferents in vitro unexpectedly causes long-term potentiation. Opioid receptor activation profoundly depresses PAG and RMTg inhibitory synapses but prevents synaptic plasticity only at PAG synapses. Activation of the GABAergic PAG terminals in the VTA promotes immobility, and optogenetically-driven immobility is blocked by morphine. Our data reveal the PAG as a source of highly opioid-sensitive GABAergic afferents and support the idea that different GABAergic pathways to the VTA control distinct behaviors.
Learn More >Amenamevir (AMNV) is a helicase-primase inhibitor with antiviral activity against herpesviruses [herpes simplex viruses (HSV)-1 and -2, and varicella-zoster virus], which are associated with the development of acute herpetic pain (AHP) and postherpetic neuralgia. However, the inhibitory effects of helicase-primase inhibitors on AHP and postherpetic neuralgia remain incompletely understood.
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