Manipulating Pharmacodynamic Efficacy with Agonist + Antagonist Mixtures: In Vitro and In Vivo Studies with Opioids and Cannabinoids.

Pharmacodynamic efficacy of drugs to activate their receptors is a key determinant of drug effects, and intermediate-efficacy agonists are often useful clinically because they retain sufficient efficacy to produce therapeutically desirable effects while minimizing undesirable effects. Molecular mechanisms of efficacy are not well understood, so rational drug design to control efficacy is not yet possible; however, receptor theory predicts that fixed-proportion mixtures of an agonist and antagonist for a given receptor can be adjusted to precisely control net efficacy of the mixture in activating that receptor. Moreover, the agonist proportion required to produce different effects provides a quantitative scale for comparing efficacy requirements across those effects. To test this hypothesis, the present study evaluated effectiveness of fixed-proportion agonist/antagonist mixtures to produce in vitro and in vivo effects mediated by µ-opioid receptors (MOR) and cannabinoid type 1 receptors (CB1R). Mixtures of 1) the MOR agonist fentanyl and antagonist naltrexone and 2) the CB1R agonist CP55,940 and antagonist/inverse agonist rimonabant were evaluated in an in vitro assay of ligand-stimulated guanosine 5'-O-(3-[35S]thio)triphosphate binding and an in vivo assay of thermal nociception in mice. For both agonist/antagonist pairs in both assays, increasing agonist proportions produced graded increases in maximal mixture effects, and lower agonist proportions were sufficient to produce in vivo than in vitro effects. These findings support the utility of agonist-antagonist mixtures as a strategy to control net efficacy of receptor activation and to quantify and compare efficacy requirements across a range of in vitro and in vivo endpoints. SIGNIFICANCE STATEMENT: Manipulation of agonist proportion in agonist/antagonist mixtures governs net mixture efficacy at the target receptor. Parameters of agonist/antagonist mixture effects can provide a quantitative metric for comparison of efficacy requirements across a wide range of conditions.

Effects of repeated treatment with monoamine-transporter-inhibitor antidepressants on pain-related depression of intracranial self-stimulation in rats.

RATIONALE: Synaptic neurotransmission with dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is terminated primarily by reuptake into presynaptic terminals via the DA, NE, and 5-HT transporters (DAT/NET/SERT, respectively). Monoamine transporter inhibitors constitute one class of drugs used to treat both depression and pain, and therapeutic effects by these compounds often require repeated treatment for days or weeks. OBJECTIVES: The present study compared antinociceptive effects produced by repeated treatment with monoamine transporter inhibitors in a preclinical assay of pain-related depression of positively reinforced operant responding. METHODS: Adult Sprague-Dawley rats equipped with microelectrodes targeting a brain-reward area responded for pulses of electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus that repeatedly depressed ICSS and also produced weight loss during 7 days of repeated acid administration. RESULTS: Acid-induced depression of both ICSS and body weight were completely blocked by repeated pretreatment with the nonsteroidal anti-inflammatory drug ketorolac. The DAT-selective inhibitor bupropion also fully blocked acid-induced ICSS depression and weight loss throughout all 7 days of treatment. The NET-selective inhibitor nortriptyline and the SERT-selective inhibitor citalopram were generally less effective, but both drugs blocked acid-induced ICSS depression by the end of the 7-day treatment. Acid-induced depression of ICSS and body weight were not blocked by the kappa opioid receptor (KOR) agonist U69593 or the KOR antagonist norbinaltorphimine. CONCLUSIONS: These results support effectiveness of bupropion to alleviate signs of pain-related behavioral depression in rats and further suggest that nortriptyline and citalopram produce significant but less reliable effects.

Repeated Morphine Produces Sensitization to Reward and Tolerance to Antiallodynia in Male and Female Rats with Chemotherapy-Induced Neuropathy.

Paclitaxel is a cancer chemotherapy drug with adverse effects that include chemotherapy-induced neuropathic pain (CINP) as well as depression of behavior and mood. In the clinical setting, opioids are often used concurrently with or after chemotherapy to treat pain related to the cancer or CINP, but repeated opioid exposure can also increase the risk of opioid abuse. In this study, male and female Sprague-Dawley rats were used to test the hypothesis that repeated 3.2-mg/kg doses of morphine would induce tolerance to its antinociceptive effects in a mechanical sensitivity assay and increased expression of its abuse-related rewarding effects in an assay of intracranial self-stimulation (ICSS). Three weeks after four injections of vehicle or 2.0 mg/kg of paclitaxel, the initial morphine dose-effect curves were determined in both assays. Subsequently, rats were treated with 3.2 mg/kg per day morphine for 6 days. On the final day of testing, morphine dose-effect curves were redetermined in both assays. On initial exposure, morphine produced dose-dependent antiallodynia in the assay of mechanical sensitivity, but it produced little or no rewarding effects in the assay of ICSS. After 6 days of repeated treatment, morphine antiallodynia decreased, and morphine reward increased. Females exhibited greater morphine reward on initial exposure than males, but repeated morphine eliminated this sex difference. These results suggest that repeated morphine may produce tolerance to therapeutically beneficial analgesic effects of morphine but increased sensitivity to abuse-related rewarding effects of morphine in subjects treated with paclitaxel.

Nicotine modulates neurogenesis in the central canal during experimental autoimmune encephalomyelitis.

Nicotine has been shown to attenuate experimental autoimmune encephalomyelitis (EAE) through inhibiting inflammation in microglial populations during the disease course. In this study, we investigated whether nicotine modified the regenerative process in EAE by examining nestin-expressing neural stem cells (NSCs) in the spinal cord, which is the primary area of demyelination and inflammation in EAE. Our results show that the endogenous neurogenic responses in the spinal cord after EAE are limited and delayed: while nestin expression is increased, the proliferation of ependymal cells is inhibited compared to healthy animals. Nicotine application significantly reduced nestin expression and partially allowed for the proliferation of ependymal cells. We found that reduction of ependymal cell proliferation correlated with inflammation in the same area, which was relieved by the administration of nicotine. Further, increased numbers of oligodendrocytes (OLs) were observed after nicotine treatment. These findings give a new insight into the mechanism of how nicotine functions to attenuate EAE.