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.

FIGURE 1

Intracranial self-stimulation (ICSS) is an operant conditioning procedure that produces stable baseline behavioral response rates for research on pain-related behavioral depression. (a) A rat equipped with an intracranial electrode that targets the brain reward pathway. During experimental sessions, the rat is placed into an operant conditioning chamber, and the electrode is connected by a cable to a stimulator (not shown). Pressing a lever in the chamber illuminates a set of stimulus lights located over the lever and activates the stimulator to deliver pulses of brain stimulation via the electrode. Rats readily learn to press the lever for brain stimulation reinforcement. (b) Illustrative baseline ‘frequency-rate’ curve for ICSS response rates. ICSS response rate (normalized and expressed as a percentage of the maximum control rate, %MCR) increases with increases in the magnitude of brain stimulation reinforcement (expressed on a log scale as the frequency of electrical stimulation in Hz). Data adapted from ref. and represent the mean ± s.e.m. of values from 34 rats.

FIGURE 2

Pain-related depression of ICSS response rate. (a) Intraperitoneal injection of 1.8% lactic acid at a dosage of 1 ml per kg body weight serves as a visceral noxious stimulus that depresses ICSS response rate across a range of brain stimulation magnitudes. Response rate was significantly lower (#P < 0.05 by two-way analysis of variance followed by Holm-Sidak post hoc test) after administration of acid than after administration of saline vehicle at a dosage of 1 ml per kg body weight (LA vehicle). (b) Administration of lactic acid significantly reduced total ICSS response rate across all stimulation magnitudes (expressed as a percentage of baseline ICSS rate determined before administration of vehicle or lactic acid; #P < 0.05) compared with administration of saline vehicle (LA vehicle). Data adapted from ref. and represent the mean ± s.e.m. of values from 34 rats.

FIGURE 3

Ketoprofen blocks acid-induced depression of ICSS response rate. In the absence of lactic acid (LA vehicle), ketoprofen had no effect on ICSS response rate (a), but in the presence of lactic acid, pretreatment with 1.0 mg ketoprofen per kg body weight blocked the acid-induced depression of ICSS response rate (b) across a range of stimulation magnitudes (*P < 0.05). At a relatively high stimulation magnitude of 141 Hz, ketoprofen blocked acid-induced depression of ICSS response rate (thick arrow in b) but had no effect on response rate in the absence of lactic acid (thick arrow in a). However, these data at 141 Hz are not sufficient to show a lack of ketoprofen effect in the absence of acid, because baseline ICSS response rate at this stimulation magnitude was near maximal in the absence of acid and could not be further increased. Consequently, it is important to note that ketoprofen also failed to increase the lower baseline ICSS response rate maintained by a lower stimulation magnitude of 112 Hz in the absence of lactic acid (thin arrow in a). (c) Lactic acid significantly depressed total ICSS response rate across all stimulation magnitudes (#P < 0.05), and ketoprofen significantly blocked the acid-induced depression of ICSS response rate (*P < 0.05). Data adapted from ref. and represent the mean ± s.e.m. of values from 4 rats.

FIGURE 4

Effects of candidate analgesic compounds on acid-induced depression of ICSS response rate. (a) Like ketoprofen, SNC80 selectively blocked acid-induced depression of ICSS response rate. Thus, SNC80 had little effect on total ICSS response rate in the absence of lactic acid but dose-dependently blocked acid-induced depression of total ICSS response rate. (b) Salvinorin A non-selectively decreased ICSS response rate. Thus, salvinorin A decreased total ICSS response rate in the absence of lactic acid and also exacerbated acid-induced depression of ICSS response rate. (c) Bupropion non-selectively increased ICSS response rate. Thus, bupropion blocked acid-induced depression of total ICSS response rate, but only at doses that also increased total ICSS response rate in the absence of lactic acid. Significant acid-induced depression of ICSS response rate (#P < 0.05) and significant differences in ICSS response rate with a given drug dose compared with no drug in either the presence or the absence of lactic acid (*P < 0.05) are indicated. Data adapted from refs. , and and represent the mean ± s.e.m. of values from 5–8 rats.