Opioid-sparing effects of cannabinoids on morphine analgesia: participation of CB and CB receptors.

Background And Purpose: Much of the opioid epidemic arose from abuse of prescription opioid drugs. This study sought to determine if the combination of a cannabinoid with an opioid could produce additive or synergistic effects on pain, allowing reduction in the opioid dose needed for maximal analgesia.

Experimental Approach: Pain was assayed using the formalin test in mice and the carrageenan assay in rats.

Single and combined effects of Δ -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain.

Background And Purpose: The non-psychoactive phytocannabinoid cannabidiol (CBD) can affect the pharmacological effects of Δ -tetrahydrocannabinol (THC). We tested the possible synergy between CBD and THC in decreasing mechanical sensitivity in a mouse model of paclitaxel-induced neuropathic pain. We also tested the effects of CBD on oxaliplatin- and vincristine-induced mechanical sensitivity.

Synergistic antidepressant-like effects between a kappa opioid antagonist (LY2444296) and a delta opioid agonist (ADL5859) in the mouse forced swim test.

Kappa opioid (KOP) receptor antagonists and delta opioid (DOP) receptor agonists have antidepressant-like effects in animal tests and may be useful for treatment-resistant depression in humans. In this study, we examined whether the combination of a KOP receptor antagonist and a DOP receptor agonist would produce a better than additive effect (i.e.

Drug Combinations: Tests and Analysis with Isoboles.

Described in this unit are experimental and computational methods to detect and classify drug interactions. In most cases, this relates to two drugs or compounds with overtly similar effects, e.g.

Levamisole enhances the rewarding and locomotor-activating effects of cocaine in rats.

Background: The Drug Enforcement Agency estimates that 80% of cocaine seized in the United States contains the veterinary pharmaceutical levamisole (LVM). One problem with LVM is that it is producing life-threatening neutropenia in an alarming number of cocaine abusers. The neuropharmacological profile of LVM is also suggestive of an agent with modest reinforcing and stimulant effects that could enhance cocaine's addictive effects.

Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice.

Cannabinoid and opioid agonists can display overlapping behavioral effects and the combination of these agonists is known to produce enhanced antinociception in several rodent models of acute and chronic pain. The present study investigated the antinociceptive effects of the nonpsychoactive cannabinoid, cannabidiol (CBD) and the µ-opioid agonist morphine, both alone and in combination, using three behavioral models in mice, to test the hypothesis that combinations of morphine and CBD would produce synergistic effects. The effects of morphine, CBD, and morphine/CBD combinations were assessed in the following assays: (a) acetic acid-stimulated stretching; (b) acetic acid-decreased operant responding for palatable food; and (c) hot plate thermal nociception.

Ethanol and cocaine: environmental place conditioning, stereotypy, and synergism in planarians.

More than 90% of individuals who use cocaine also report concurrent ethanol use, but only a few studies, all conducted with vertebrates, have investigated pharmacodynamic interactions between ethanol and cocaine. Planaria, a type of flatworm often considered to have the simplest 'brain,' is an invertebrate species especially amenable to the quantification of drug-induced behavioral responses and identification of conserved responses. Here, we investigated stereotypical and environmental place conditioning (EPC) effects of ethanol administered alone and in combination with cocaine.

Combining opioid and adrenergic mechanisms for chronic pain.

Chronic pain is a highly prevalent medical problem in the United States. Although opioids and serotonin-norepinephrine reuptake inhibitors (SNRIs) have demonstrated efficacy for relief of chronic pain, each has risks of adverse events in patients. Because of the risk of opioid abuse and addiction, combinations reducing opioid requirements are particularly valuable.

Lack of synergistic interaction between the two mechanisms of action of tapentadol in gastrointestinal transit.

Background: A multi-mechanistic approach offers potential enhancement of analgesic efficacy, but therapeutic gain could be offset by an increase in adverse events. The centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and neuronal noradrenaline reuptake inhibition (NRI), both of which contribute to its analgesic effects. Previously, isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated pronounced synergistic interaction between the two mechanisms of action of tapentadol in two models of antinociception (low-intensity tail-flick and spinal nerve ligation).

Levamisole and cocaine synergism: a prevalent adulterant enhances cocaine's action in vivo.

Levamisole is estimated by the Drug Enforcement Agency (DEA) to be present in about 80% of cocaine seized in the United States and linked to debilitating, and sometimes fatal, immunologic effects in cocaine abusers. One explanation for the addition of levamisole to cocaine is that it increases the amount of product and enhances profits. An alternative possibility, and one investigated here, is that levamisole alters cocaine's action in vivo.

Spinal-supraspinal and intrinsic μ-opioid receptor agonist-norepinephrine reuptake inhibitor (MOR-NRI) synergy of tapentadol in diabetic heat hyperalgesia in mice.

Tapentadol is a μ-opioid receptor (MOR) agonist and norepinephrine reuptake inhibitor (NRI) with established efficacy in neuropathic pain in patients and intrinsic synergistic interaction of both mechanisms as demonstrated in rodents. In diabetic mice, we analyzed the central antihyperalgesic activity, the occurrence of site-site interaction, as well as the spinal contribution of opioid and noradrenergic mechanisms in a hotplate test. Tapentadol (0.

Methylphenidate and impulsivity: a comparison of effects of methylphenidate enantiomers on delay discounting in rats.

Rationale: Current formulations of methylphenidate (MPH) used in treatment of attention-deficit/hyperactivity disorder (ADHD) result in significantly different bioavailability of MPH enantiomers. Daytrana®, a dl-MPH transdermal patch system, produces higher levels of l-MPH than when dl-MPH is administered orally (e.g.

A search for interaction among combinations of drugs of abuse and the use of isobolographic analysis.

What Is Known And Objective: Individuals who abuse drugs usually use more than one substance. Toxic consequences of single and multi-drug use are well documented in the Treatment Episodes Data Set that lists drug combinations that result in hospital admissions. Using this list as a guide, we focused our attention on combinations that result in the most hospital admissions and searched the PubMed database with the objective of determining the number of such publications and, in particular, those that used the term synergism in their titles or abstracts.

Cocaine synergism with α agonists in rat aorta: computational analysis reveals an action beyond reuptake inhibition.

Background: Cocaine has long been known to increase blood pressure, but the degree and mechanism of vasoconstricting action remain poorly understood. Here we examine the interaction between cocaine and alpha-adrenoceptor agonists, with the action of reuptake inhibition minimized.

Methods: Cocaine was administered to isolated rings of rat thoracic aorta, alone and in combination with three different adrenoceptor agonists: phenylephrine, methoxamine, and norepinephrine.

Quantitative methods for assessing drug synergism.

Two or more drugs that individually produce overtly similar effects will sometimes display greatly enhanced effects when given in combination. When the combined effect is greater than that predicted by their individual potencies, the combination is said to be synergistic. A synergistic interaction allows the use of lower doses of the combination constituents, a situation that may reduce adverse reactions.

Revisiting the isobole and related quantitative methods for assessing drug synergism.

The isobole is well established and commonly used in the quantitative study of agonist drug combinations. This article reviews the isobole, its derivation from the concept of dose equivalence, and its usefulness in providing the predicted effect of an agonist drug combination, a topic not discussed in pharmacology textbooks. This review addresses that topic and also shows that an alternate method, called "Bliss independence," is inconsistent with the isobolar approach and also has a less clear conceptual basis.

Fixed-dose combinations for emerging treatment of pain.

Introduction: Pain is a large and growing medical need that is not currently being fully met, primarily due to the shortcomings of existing analgesics (insufficient efficacy or limiting side-effects). Better outcomes might be achieved using a combination of analgesics. The ratio of the combinations matters and should therefore be evaluated using rigorous quantitative and well-documented analysis.

Mephedrone ("bath salt") pharmacology: insights from invertebrates.

Psychoactive bath salts (also called meph, drone, meow meow, m-CAT, bounce, bubbles, mad cow, etc.) contain a substance called mephedrone (4-methylcathinone) that may share psychostimulant properties with amphetamine and cocaine. However, there are only limited studies of the neuropharmacological profile of mephedrone.

'Null method' determination of drug biophase concentration.

PK/PD modeling is enhanced by improvements in the accuracy of its metrics. For PK/PD modeling of drugs and biologics that interact with enzymes or receptors, the equilibrium constant of the interaction can provide critical insight. Methodologies such as radioliogand binding and isolated tissue preparations can provide estimates of the equilibrium constants (as the dissociation constant, K value) for drugs and endogenous ligands that interact with specific enzymes and receptors.

On the quantitation of an agonist with dual but opposing components of action: application to vascular endothelial relaxation.

In this communication we show that the same principle that underlies the use of the isobolograph for assessing agonist interactions also leads to a method for analyzing the opposing effects of a single agonist. This is the principle of dose equivalence whose application is illustrated here and applied to the endothelium-dependent relaxing component of two putative vasoconstrictor peptides. These studies, employing angiotensin II and endothelin-1, were conducted with isolated preparations of rat aorta that were measured for agonist-induced isometric tension development in both endothelial-denuded and -intact vessels.

Continuous multimechanistic postoperative analgesia: a rationale for transitioning from intravenous acetaminophen and opioids to oral formulations.

Good surgical outcomes depend in part on good pain relief, allowing for early mobilization, optimal recovery, and patient satisfaction. Postsurgical pain has multiple mechanisms, and multimechanistic approaches to postoperative analgesia are recommended and may be associated with improved pain relief, lowered opioid doses, and sometimes a lower rate of opioid-associated side effects. Acetaminophen (paracetamol) is a familiar agent for treating many types of pain, including postsurgical pain.

Synergistic antihypersensitive effects of pregabalin and tapentadol in a rat model of neuropathic pain.

Neuropathic pain is a clinical condition which remains poorly treated and combinations of pregabalin, an antagonist of the α2δ-subunit of Ca(2+) channels, with tapentadol, a μ-opioid receptor agonist/noradrenaline reuptake inhibitor, or with classical opioids such as oxycodone and morphine might offer increased therapeutic potential. In the rat spinal nerve ligation model, a dose dependent increase in ipsilateral paw withdrawal thresholds was obtained using an electronic von Frey filament after IV administration of pregabalin (1-10mg/kg), tapentadol (0.316-10mg/kg), morphine (1-4.

Resveratrol in combination with other dietary polyphenols concomitantly enhances antiproliferation and UGT1A1 induction in Caco-2 cells.

Aims: The only FDA approved medication for colorectal cancer (CRC) prevention is celecoxib. Its adverse effects underline the need for safer drugs. Polyphenols like resveratrol are in clinical trials for this purpose.

Synergistic interaction between the two mechanisms of action of tapentadol in analgesia.

The novel centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines two mechanisms of action, μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms.