Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Abstract

Opioid receptor agonists that do not readily cross the bloodbrain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central receptors. The present study used assays of painrelated stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted agonists [the, 2) a centrally penetrating agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal antiinflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted agonists had little effect, and salvinorin A exacerbated acidinduced depression of ICSS. These results suggest that peripherally restricted agonists may be safer than centrally penetrating agonists but less efficacious than NSAIDS or opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with agonists capable of greater peripheral selectivity are warranted.

Pain-Related Depression of the Mesolimbic Dopamine System in Rats: Expression, Blockade by Analgesics, and Role of Endogenous κ-opioids

“…Specifically, ketoprofen (3.2 mg/kg), morphine (3.2 mg/kg), or vehicle was administered subcutaneously 30 min before intraperitoneal administration of dilute lactic acid (5.6% in 1 ml/kg), U69593 (0.56 mg/kg), or vehicle, and DA levels were recorded at 6-min intervals for 120 min. A higher ketoprofen dose (3.2 mg/kg) was used here than previously (1.0 mg/kg; Negus et al, 2012) because of the higher intensity noxious stimulus (5.6% vs 1.8% lactic acid, respectively). The dose of U69593 was selected based on preliminary studies to identify a dose that produced depression of mesolimbic DA to a degree comparable to that produced by lactic acid.…”

“…Training continued with presentation of three sequential components per day, and intensity was again adjusted as necessary until rats reliably responded for at least three and no more than six trials of all components for at least two consecutive days. Testing was conducted using drugs, doses, and pretreatment times identical to those used in microdialysis experiments, and as noted above, these parameters were based on previous studies from our laboratory (Altarifi and Negus, 2011;Negus et al, 2010bNegus et al, , 2012. ICSS test sessions consisted of seven sequential components.…”

“…DA levels were considered to have stabilized after collection of 10 consecutive baseline samples with o10% variability around the running mean. Testing was conducted using drugs, doses, and pretreatment times based on previous behavioral studies from our laboratory (see below; (Altarifi and Negus, 2011;Negus et al, 2010b;Negus et al, 2012)). Specifically, ketoprofen (3.2 mg/kg), morphine (3.2 mg/kg), or vehicle was administered subcutaneously 30 min before intraperitoneal administration of dilute lactic acid (5.6% in 1 ml/kg), U69593 (0.56 mg/kg), or vehicle, and DA levels were recorded at 6-min intervals for 120 min.…”

“…administration of exogenous acid functions as one type of physiologically relevant noxious visceral stimulus that depresses ICSS (Pereira Do Carmo et al, 2009;Negus, 2013). In addition, acid-induced depression of ICSS can be blocked by clinically effective analgesics including both m-opioid agonists such as morphine and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen (Kwilasz and Negus, 2012;Negus et al, 2010aNegus et al, , 2012Pereira Do Carmo et al, 2009). Taken together, these observations suggest that acid-induced depression of ICSS may serve as a useful model for research on mechanisms of pain-related depression of behavior and brain reward systems.…”

“…Ventral tegmental area DA neurons receive inputs from dynorphinergic neurons and express k-receptors, and activation of these k-receptors depresses neuronal activity and DA release (Knoll and Carlezon, 2010;Wee and Koob, 2010). For example, exogenous k-agonists such as salvinorin A and U69593 decrease both mesolimbic DA release and behaviors such as ICSS that depend on mesolimbic DA release (Carlezon et al, 2006;Di Chiara and Imperato, 1988b;Negus et al, 2012;Todtenkopf et al, 2004;Zhang et al, 2005). Moreover, recent studies suggest that some nonnoxious stressors (eg, forced swim in rats) activate dynorphin/k-systems to produce depressive-like effects that can be blocked by k-opioid receptor antagonists (Bruchas et al, 2010;Chartoff et al, 2009;McLaughlin et al, 2003).…”