Biomedical subjects

Kirsten M Raehal

Publications and source records attributed to Kirsten M Raehal.

5 recordsLinked to original sources

PubMed2006

Opioid receptor signaling: relevance for gastrointestinal therapy.

Opiate drugs, such as morphine, are renowned for their analgesic properties. To date, opioid narcotics represent the largest and most potent class of pain relievers available to treat both acute and chronic pain conditions. The use of opiates, however, is severely limited by several adverse side effects. Upon chronic use, opiates can produce tolerance, physical dependence and addiction. Although these conditions warrant consideration, there are acute effects that present more immediate concerns when choosing opiate narcotics for pain therapy. One of the most prevalent side effects, which continues for as long as the opiate is used for pain control, is constipation. This can impact patient compliance, as it is often one of the top reasons why patients discontinue opiate treatment. The challenge, therefore, is to develop pain therapies that preserve potent analgesia while preventing constipation.

Constipation↗

PubMed2005

Mu opioid receptor regulation and opiate responsiveness.

Opiate drugs such as morphine are well known for their ability to produce potent analgesia as well as such unwanted side effects as tolerance, physical dependence, respiratory suppression and constipation. Opiates act at opioid receptors, which belong to the family of G protein-coupled receptors. The mechanisms governing mu opioid receptor (muOR) regulation are of particular interest since morphine and other clinically important analgesics produce their pharmacological effects through this receptor. Here we review recent advances in understanding how opioid receptor regulation can impart differential agonist efficacy produced in vivo.

Analgesics, Opioid↗

PubMed2005

Morphine side effects in beta-arrestin 2 knockout mice.

Morphine is a potent analgesic, yet, like most opioid narcotics, it exerts unwanted side effects such as constipation and respiratory suppression, thereby limiting its clinical utility. Pharmacological approaches taken to preserve the analgesic properties, while eliminating the unwanted side effects, have met with very limited success. Here, we provide evidence that altering mu opioid receptor regulation may provide a novel approach to discriminate morphine's beneficial and deleterious effects in vivo. We have previously reported that mice lacking the G protein-coupled receptor regulatory protein, beta-arrestin 2, display profoundly altered morphine responses. beta-Arrestin 2 knockout mice have enhanced and prolonged morphine analgesia with very little morphine tolerance. In this report, we examine whether the side effects of morphine treatment are also augmented in this animal model. Surprisingly, the genetic disruption of opioid receptor regulation, while enhancing and prolonging analgesia, dramatically attenuates the respiratory suppression and acute constipation caused by morphine.

Animals↗

PubMed2005

In vivo characterization of 6beta-naltrexol, an opioid ligand with less inverse agonist activity compared with naltrexone and naloxone in opioid-dependent mice.

The mu-opioid receptor displays basal signaling activity, which seems to be enhanced by exposure to opioid agonists. This study assesses the in vivo pharmacology of the putative "neutral" antagonist 6beta-naltrexol in comparison to other ligands with varying efficacy, such as naloxone, an inverse agonist in the opioid-dependent state. ICR mice were used to generate full antagonist dose-response curves for naloxone, naltrexone, nalbuphine, and 6beta-naltrexol in blocking acute antinociceptive effects of morphine and precipitating opioid withdrawal in models of physical dependence. 6beta-Naltrexol was roughly equipotent to naloxone and between 4.5- and 10-fold less potent than naltrexone in blocking morphine-induced antinociception and locomotor activity, showing that 6beta-naltrexol enters the central nervous system. In contrast to naloxone and naltrexone, 6beta-naltrexol precipitated only minimal withdrawal at high doses in an acute dependence model and was approximately 77- and 30-fold less potent than naltrexone and naloxone, respectively, in precipitating withdrawal in a chronic dependence model. 6beta-Naltrexol reduced the inverse agonist effects of naloxone in vitro and in vivo, as expected for a neutral antagonist. Therefore, the pharmacological effects of 6beta-naltrexol differ markedly from those of naloxone and naltrexone in the opioid-dependent state. A reduction of withdrawal effects associated with neutral mu-opioid receptor antagonists may offer advantages in treating opioid overdose and addiction.

Animals↗

PubMed2003

Basal signaling activity of mu opioid receptor in mouse brain: role in narcotic dependence.

Narcotic analgesics cause addiction by poorly understood mechanisms, involving mu opoid receptor (MOR). Previous cell culture studies have demonstrated significant basal, spontaneous MOR signaling activity, but its relevance to narcotic addiction remained unclear. In this study, we tested basal MOR-signaling activity in brain tissue from untreated and morphine-pretreated mice, in comparison to antagonist-induced withdrawal in morphine-dependent mice. Using guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTP gamma S) binding and adenylyl cyclase activity assay in brain homogenates, we demonstrated that morphine pretreatment of mice enhanced basal MOR signaling in mouse brain homogenates and, moreover, caused persistent changes in the effects of naloxone and naltrexone, antagonists that elicit severe withdrawal in dependent subjects. Naloxone and naltrexone suppressed basal [(35)S]GTP gamma S binding (acting as "inverse agonists") only after morphine pretreatment, but not in drug-naive animals. Moreover, naloxone and naltrexone stimulated adenylyl cyclase activity in striatum homogenates only after morphine pretreatment, by reversing the inhibitory effects of basal MOR activity. After cessation of morphine treatment, the time course of inverse naloxone effects on basal MOR signaling was similar to the time course of naltrexone-stimulated narcotic withdrawal over several days. The neutral antagonist 6 beta-naltrexol blocked MOR activation without affecting basal signaling (G protein coupling and adenylyl cyclase regulation) and also elicited substantially less severe withdrawal. These results demonstrate long-lasting regulation of basal MOR signaling as a potential factor in narcotic dependence.

Adenylyl Cyclases↗