Expression and treatment of pain-related behavioral depression

Abstract

Pain is often associated with clinically relevant depression of behavior and mood, and relief of pain-related depression is a common goal of treatment in both human and veterinary medicine. In the development of pharmacological compounds to treat pain and related depression, preclinical studies may be used to evaluate the analgesic potential of new drugs. Such studies require reliable, accurate assays of pain-related behavioral depression in animals. Intracranial self-stimulation (ICSS) is a type of operant conditioning procedure that produces stable baseline behavioral response rates. The author reviews recent research on the use of ICSS to evaluate the expression and pharmacological modulation of pain-related behavioral depression in rats. Results suggest that assays of pain-depressed behavior using ICSS may serve as a useful new tool to improve the translation of preclinical findings to clinical results in analgesic drug development.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…Noxious Stimulation and Pain. In contrast to the enhancement of basal ICSS produced by food deprivation, noxious stimulation and associated pain states can produce a depression of basal ICSS (Negus, 2013). For example, tissue acidification is a common component of inflammation, and intraperitoneal injection of dilute acid is a well-established chemical noxious stimulus that produces a concentration-and timedependent depression of ICSS in rats responding under a hybrid frequency-rate procedure (Pereira Do Carmo et al, 2009).…”

Effects of μ-Opioid Receptor Agonists in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Male Rats: Role of μ-Agonist Efficacy and Noxious Stimulus Intensity

“…Most preclinical assays of antinociception rely on measurements of "pain-stimulated behaviors," which can be defined as behaviors that increase in rate, frequency, or intensity after noxious stimulus presentation Stevenson et al, 2006;Negus, 2013). Common examples include withdrawal responses from stimuli that can be escaped (e.g., tail withdrawal from thermal stimuli) or pseudowithdrawal responses from stimuli that cannot be escaped (e.g., stretching responses elicited by intraperitoneal injection of chemical stimuli).…”

“…In accordance with the clinical importance of pain-related behavioral depression, we have argued that analgesic drug development might benefit from preclinical assays of "paindepressed behaviors," which can be defined as behaviors that decrease in rate, frequency, or intensity after noxious stimulus presentation (Negus, 2013). We recently showed in rats that a commonly used and physiologically relevant noxious stimulus (intraperitoneal injection of diluted acid) could both stimulate a stretching response and depress intracranial self-stimulation (ICSS) (a positively reinforced operant behavior in which leverpress responding is maintained by delivery of electrical brain stimulation) Negus et al, 2010a;Altarifi et al, 2013;Negus, 2013;Negus and Altarifi, 2013).…”

“…We recently showed in rats that a commonly used and physiologically relevant noxious stimulus (intraperitoneal injection of diluted acid) could both stimulate a stretching response and depress intracranial self-stimulation (ICSS) (a positively reinforced operant behavior in which leverpress responding is maintained by delivery of electrical brain stimulation) Negus et al, 2010a;Altarifi et al, 2013;Negus, 2013;Negus and Altarifi, 2013). Both acidstimulated stretching and acid-induced depression of ICSS could be blocked by clinically effective analgesics such as the m-opioid receptor agonist morphine and the nonsteroidal antiinflammatory drug ketoprofen.…”

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

“…Tissue acidosis is a cardinal component of inflammation that contributes to nociception and pain (Bray et al, 2013;Deval et al, 2013), and intraperitoneal (i.p.) 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).…”