Effects of pain- and analgesia-related manipulations on intracranial self-stimulation in rats: further studies on pain-depressed behavior

Abstract

Pain stimulates some behaviors (e.g., withdrawal responses) but depresses many other behaviors (e.g., feeding). Pain-stimulated behaviors are widely used in preclinical research on pain and analgesia, but human and veterinary medicine often rely on measures of functional impairment and pain-depressed behavior to diagnose pain or assess analgesic efficacy. In view of the clinical utility of measures of pain-depressed behaviors, our laboratory has focused on the development of methods for preclinical assays of pain-depressed behavior in rodents. The present study compared the effects of a chemical noxious stimulus (IP lactic acid injections) and an opioid analgesic (morphine) administered alone or in combination on the stretching response (a pain-stimulated behavior) and intracranial self-stimulation (ICSS; a behavior that may be depressed by pain) in rats. In the ICSS procedure, rats implanted with electrodes in the lateral hypothalamus responded to electrical stimulation across a range of current frequencies to permit rapid determination of frequency-rate curves and evaluation of curve shifts following treatment. Lactic acid alone produced a concentration-dependent stimulation of stretching and depression of ICSS, expressed as rightward shifts in ICSS frequency-rate curves. Morphine had little effect alone, but it produced a dose-dependent blockade of both acid-stimulated stretching and acid-depressed ICSS. Both lactic acid and morphine were equipotent in the stretching and ICSS procedures. These results suggest that ICSS may be useful as a behavioral baseline for studies of pain-depressed behavior.

Figure 1

Effect of lactic acid (1–3.2 %, IP) on ICSS in rats. All data points show mean data ± S.E.M. from five rats except where indicated by numbers in parentheses. In these cases, the number indicates the number of rats in which ΔEF50 values could be calculated. (A) Time course of effects on ΔEF50. Abscissa: Time in min after acid injection. Ordinate: ΔEF50 in log Hz. (B) Time course of effects on Peak % MCR. Abscissa: Time in min after acid injection. Ordinate: Peak % MCR. (C) Dose-effect curve at time of peak effect on ΔEF50 (30 min). Abscissa: Lactic acid concentration (log scale). Left ordinate: ΔEF50. Right ordinate: Peak %MCR. (D) Selected log frequency-rate curves. Abscissa: Log frequency of electrical stimulation in Hz. Ordinate: Response rate in responses per min. Curves are shown for representative baseline data and for data collected 30 min after administration of 1.8% lactic acid. ^*P<0.05, 1.8 % lactic acid compared to baseline, ^#P<0.05, 3.2 % lactic acid compared to saline; Bonferroni’s post hoc.

Figure 2

The effects of saline or morphine (1–5.6 mg/kg, IP) on ICSS in rats. All data points show mean data ± S.E.M. from 5 rats except where indicated by numbers in parentheses. In these cases, the number indicates the number of rats in which ΔEF50 values could be calculated. (A) Time course of effects on ΔEF50. Abscissa: Time in min after drug injection. Ordinate: ΔEF50 in log Hz (B) Time course of effects on Peak % MCR. Abscissa: Time in min after drug injection. Ordinate: Peak % MCR. (C) Dose-effect curve at time of peak effect of morphine on response rates (45 min). Abscissa: Dose of morphine in mg/kg (log scale). Left ordinate: ΔEF50. Right ordinate: Peak %MCR. (D) Selected log frequency-rate curves. Abscissa: Log frequency of electrical stimulation in Hz. Ordinate: Response rate in responses per min. Curves are shown for representative baseline data and for data collected 45 min after administration of 3.2 mg/kg morphine. ^§Indicates that statistical analyses on ΔEF50 values could not be performed with the 5.6 mg/kg morphine treatment group between the 30–90 min time points because ΔEF50 values could not be calculated in two rats.

Figure 3

The effects of lactic acid alone (1.8%, IP) or 30 min after pretreatment with morphine (0.1–3.2 mg/kg, IP) on ICSS in rats. All data points show mean data ± S.E.M. from five rats. (A) Time course of effects on Δ EF50. Abscissa: Time in min after lactic acid injection. Ordinate: ΔEF50 in log Hz. (B) Time course of effects on Peak % MCR. Abscissa: Time in min after lactic acid injection. Ordinate: Peak % MCR. (C) Dose-effect curve at time of peak morphine effect on lactic acid-elevated ΔEF50 values (45 min). Abscissa: Dose of morphine in mg/kg (log scale) administered as a pretreatment to 1.8% lactic acid. Left ordinate: ΔEF50. Right ordinate: Peak %MCR. (D) Selected log frequency-rate curves. Abscissa: Log frequency of electrical stimulation in Hz. Ordinate: Response rate in responses per min. Curves are shown for representative baseline data and for data collected 45 min after administration of 3.2 mg/kg morphine + 1.8% lactic acid. ^*P<0.05, 1.8 % lactic acid compared to baseline, ^δP<0.05, 1.0 mg/kg morphine + 1.8 % lactic acid compared to 1.8% lactic acid alone, ^#P<0.05, 3.2 mg/kg morphine + 1.8 % lactic acid compared to 1.8% lactic acid alone; Bonferroni’s post hoc.

Figure 4

Left panel: The effects of saline or lactic acid (0.32 – 3.2 %, IP) on the expression of stretching in rats. All data points show mean data ± S.E.M. from four rats. (A) Abscissa: Time after lactic acid injection (per 10 min bins). Ordinate: Number of stretches. ^*P<0.05, 1.8 % lactic acid compared to saline, ^#P<0.05, 3.2 % lactic acid compared to saline; Bonferroni’s post hoc. Right panel: The effects of morphine (0.1–3.2 mg/kg, IP) + lactic acid (1.8%, IP) on stretching in rats. All data points show mean data ± S.E.M. from four rats. (B) Abscissa: Dose of morphine in mg/kg administered 30 min before lactic acid. Ordinate: Number of stretches during 30 min observation period. ^*P<0.05, 1.0 and 3.2 mg/kg morphine + lactic acid compared to lactic acid alone; Bonferroni’s post hoc.