Current Neuropharmacology - Volume 2, Issue 4, 2004

There are many reports showing prominent interactions between α2 adrenoceptor ligands and opioid drugs. This paper discusses these studies and the evidence available for their potential therapeutic applications. In acute conditions, α2-adrenoceptor antagonists inhibit some of the central and peripheral effects of opioids, while agonists have additive or synergistic effects that can be useful in enhancing opioid analgesia. Chronic administration of prescribed or illegal opioids leads to biological adaptations that influence the function of α2 adrenoceptors, which can be significantly modified by the ligands of these receptors: thus, cross-tolerance has been described between opioid and α2 agonists, and these latter drugs effectively block the manifestations of opioid withdrawal in animals and humans. Conversely, α2- adrenoceptor antagonists prevent the development of tolerance or dependence when coadministered with chronic opioids and increase withdrawal signs when acutely injected to abstinent subjects. There are also preclinical and clinical data showing that α2-adrenoceptor ligands could modify the appetitive and motivational properties of opioid drugs: agonists tend to increase these addictive properties, while the antagonist yohimbine has been shown to decrease opioid reinforcement in place conditioning studies. Interestingly, α2-adrenoceptor agonists prevent the reinstatement of opioid and cocaine self-administration induced by stress. All these studies tend to show that, if properly used, α2-adrenoceptor ligands could be useful both to potentiate the beneficial effects of opioids, and to limit the complications of opioid tolerance, dependence and addiction.

Post stroke depression or PSD is believed to occur in ten to forty percent of all patients who survive stroke. These mood disturbances overlap with primary major depressive disorder in terms of symptom profile, natural history and response to antidepressant medications. Cognitive changes, especially impairments in executive functions, are commonly encountered in PSD. This may be the result of disruption to fronto-thalamo-cortical circuits in PSD. Both functional limitations following stroke and biological mechanisms may play important roles in the pathophysiology of PSD. Antidepressants are clinically effective in managing these mood disturbances and may have an important role in the prophylaxis of depression following stroke. PSD provides a naturalistic model that facilitates the study of the clinical correlates and neurobiological mechanisms that may be relevant in the pathophysiology of vascular depression.

Distribution, pharmacological and knockdown studies point to a role of group I receptors in nociceptive processing. mGlu1 and mGlu5 receptors are expressed on peripheral sensory afferents, in dorsal root ganglion neurons, dorsal and ventral horn of spinal cord, rostral ventromedial medulla, periaqeductal gray, amygdala, and ventrobasal thalamus. These receptors are functional: sensory neurons in these regions respond to pain stimuli and / or to mGlu1 and mGlu5 agonists. Intrathecal administration of group I agonists evokes spontaneous pain behaviour. Whereas mGlu1 / 5 antagonists do not alter normal sensation, their effect on acute nociception is controversial. Activation of spinal and peripheral mGlu1 or mGlu5 receptors is sufficient to evoke hyperalgesia and allodynia. Blockade of spinal or peripheral mGlu1 or peripheral mGlu5 receptors was antihyperalgesic in animal models of inflammatory pain. Although the role of supraspinal, spinal and peripheral mGlu1 and mGlu5 receptors in the development and maintenance of neuropathic pain states is not fully elucidated, spinal mGlu1 receptor blockade is effective in all pain states tested. In the periaqueductal gray, a group I agonist attenuates nociceptive responses, indicating that mGlu1 and / or mGlu5 receptors in this structure can activate the descending pathway to dampen pain. The data indicate that mGlu1 and mGlu5 antagonists have therapeutic potential for the treatment of chronic inflammatory and neuropathic pain states. More potent and bioavailable mGlu1 versus mGlu5 antagonists are needed to provide proof of concept.

Buprenorphine, an opioid with mixed agonist-antagonist activity at classical opioid receptors, has been approved recently for the treatment of opioid dependency. Buprenorphine is also used as an analgesic. The buprenorphine dose-response curve is sometimes submaximal, or even bell-shaped, in nociceptive assays, depending upon the nature and intensity of the noxious stimulus. Moreover, buprenorphine, when administered with full agonists, such as morphine, antagonizes the action of these drugs. Partial agonism at the mu opioid receptor and, in some cases, antagonism at the kappa or delta opioid receptor have been considered as possible underlying mechanisms for the ceiling effect and bell-shaped dose-response curve of buprenorphine. While ceiling effects can be explained by partial agonist activity of buprenorphine, the bell-shaped dose-response curve cannot be a consequence of this property of the drug. Recently, buprenorphine has been shown to activate the opioid receptor-like (ORL-1; also known as NOP) receptor. Supraspinal activation of the ORL-1 receptor counteracts the antinociceptive and rewarding actions of morphine, raising the possibility that these actions of buprenorphine can also be altered by its ability to concomitantly activate the ORL-1 receptor. The use of molecular biological techniques has advanced our knowledge regarding the role of opioid receptors in modulation of pain and reward. In particular, generation of opioid receptor knockout mice has proven useful in this regard. Indeed, using knockout mice, we have recently shown that the antinociceptive effect of buprenorphine mediated primarily by the mu opioid receptor is attenuated by the ability of the drug to activate the ORL-1 receptor. Thus, the goal of this review is to provide evidence demonstrating that the ORL-1 receptor plays a functional role not only in the antinociceptive effect of buprenorphine but also in other actions of the drug as well.

During pre- and early postnatal development, the neurotransmitter serotonin (5-HT) modulates cell proliferation, migration and programmed cell death, as well as cell shape and cell-cell coupling. These “trophic” effects of 5-HT, involving the cytoskeletal function, the cell cycle, and programmed cell death, can be both dependent and independent of the changes in resting membrane potential that typically define neurotransmitter action. The morphogenetic role of 5-HT is neither limited to the central nervous system (CNS), nor does it impinge upon just a single aspect of cell biology. Ontogenic differences in regional and temporal expression patterns of 5-HT receptors mediating these effects in different systems add further complexity. This review summarizes neurobiological evidence for the trophic involvement of 5-HT during development and discusses related medical issues, including potential teratological risks and possible novel therapeutic indications of selective serotonin reuptake inhibitor (SSRI) administration.

This review presents a link between histamine and epilepsy and provides the experimental evidence available so far on the effect of histamine and histaminergic agents in various seizure models. Agents that deplete brain histamine potentiate experimental convulsions while those enhancing tend to have anticonvulsant effects. Such effects are shown to be mediated via H1 and / or H3 but not H2 receptors. Lately, a large number of selective ligands for H3-receptors have been developed. Antagonists of these receptors have shown encouraging anticonvulsant effects in animal models and hold promise for potential therapeutic applications.