Opioid selective antinociception following microinjection into the periaqueductal gray of the rat.

UNLABELLED: Morphine and fentanyl produce antinociception in part by binding to mu-opioid receptors in the periaqueductal gray (PAG). The present study tested the hypothesis that the PAG also contributes to the antinociceptive effects of other commonly used opioids (oxycodone, methadone, and buprenorphine). Microinjection of high doses of oxycodone (32-188 µg/.4 µL) into the ventrolateral PAG of the rat produced a dose-dependent increase in hot plate latency. This antinociception was evident within 5 minutes and nearly gone by 30 minutes. In contrast, no antinociception was evident following microinjection of methadone or buprenorphine into the ventrolateral PAG despite use of a wide range of doses and test times. Antinociception was evident following subsequent microinjection of morphine into the same injection sites or following systemic administration of buprenorphine, demonstrating that the injections sites and drugs could support antinociception. Antinociception to systemic, but not PAG, administration of buprenorphine occurred in both male and female rats. These and previous data demonstrate that the mu-opioid receptor signaling pathway for antinociception in the PAG is selectively activated by some commonly used opioids (eg, morphine, fentanyl, and oxycodone) but not others (eg, methadone or buprenorphine). The fact that methadone and buprenorphine produce antinociception following systemic administration demonstrates that mu-opioid receptor signaling varies depending on location in the nervous system. PERSPECTIVE: This study demonstrates that the PAG contributes to the antinociceptive effects of some commonly used opioids (morphine, fentanyl, and oxycodone) but not others (methadone or buprenorphine). Such functional selectivity in PAG-mediated opioid antinociception helps explain why the analgesic profile of opioids is so variable.

Modulation of group III metabotropic glutamate receptors by hydrogen ions.

Protons act as neuromodulators and produce significant effects on synaptic transmission. The molecular basis of neuromodulation by extracellular protons is partially explained by their effects on certain neurotransmitter receptors and ion channels. The metabotropic glutamate receptors (mGluRs) are a family of eight receptor subtypes that are widely expressed throughout the mammalian CNS. In this study, the effects of physiologically relevant changes in extracellular pH were examined in mammalian cells expressing the mGluR subtypes: human mGluR1a, mGluR4a, mGluR5d or mGluR8b. The signal transduction coupling properties of mGluR4a and mGluR8b were switched from the adenylate cyclase (G(i)) pathway to the phospholipase C (G(q)) pathway by coexpression of a promiscuous G protein. Fluorometric imaging plate reader was used to measure changes in cytoplasmic calcium concentrations in response to agonist. Extracellular acidification from pH 8.0 to pH 6.5 progressively diminished mGluR4 responsiveness to the agonists L-glutamate and (2S,1'S,2'R)-2-(carboxycyclopropyl)glycine (L-CCG-I), and this inhibition was characterized by insurmountable antagonism. By comparison, extracellular acidification did not significantly alter mGluR8 responses to agonists. Furthermore, agonist activation of mGluR1a and mGluR5d was virtually unaffected by changes in pH. Because mGluR4 is expressed presynaptically and its activation inhibits the release of neurotransmitters such as glutamate and GABA, we propose that the net effect of proton inhibition of mGluR4 would be to reverse or prevent that suppression of neurotransmitter release. As such, local decreases in pH could have significant effects on the regulation of transmitter release and synaptic tone via modulation of mGluR4.

Recent advances in non-competitive mGlu5 receptor antagonists and their potential therapeutic applications.

Extensive research into the functions of glutamate and glutamate receptors in the central nervous system (CNS) has shown an essential role of metabotropic glutamate (mGlu) receptors in normal brain functions, but also in neurological and psychiatric disorders. The precise functions of these receptors remain undefined, and progress toward understanding their functions has been hampered by the lack of selective ligands with appropriate pharmacokinetic properties. The Group I mGlu receptor, mGlu5, is well positioned to regulate and fine-tune neuronal excitability and synaptic transmission through its modulation of various signal transduction pathways and interactions with other transmitter systems. Therefore, the mGlu5 receptor may be an important therapeutic target for the treatment of disorders of the central nervous system. The discovery of MPEP 3, a non-competitive mGlu5 receptor antagonist, provided a potent, selective, systemically active tool compound for proof of concept studies in animal models of various disease states. These studies have led to greater understanding of possible therapeutic applications of mGlu5 receptor antagonists in recent years, suggesting their use in a number of disease states, including chronic pain, various psychiatric and neurological disorders, substance abuse and withdrawal, obesity and gastroesophageal reflux disease (GERD). Together, these findings have intensified efforts to find other non-competitive mGlu5 receptor antagonists and have led to the discovery of several second-generation compounds, a few of which are in preclinical evaluations. There have been several recent reviews on mGlu receptor. This article highlights recent efforts on the design, synthesis and development of novel, non-competitive mGlu5 receptor antagonists and studies to understand their in vitro mechanisms of action and in vivo pharmacological profiles. Emphasis is also given to recent advances in the potential therapeutic applications of non-competitive mGlu5 receptor antagonists.