Differential tolerance to morphine antinociception in assays of pain-stimulated vs. pain-depressed behavior in rats

Abstract

In preclinical research on pain and analgesia, noxious stimuli can stimulate expression of some behaviors (e.g. withdrawal reflexes) and depress others (e.g. feeding, locomotion, and positively reinforced operant responding). Tolerance to morphine antinociception is a robust and reliable phenomenon in preclinical assays of pain-stimulated behavior, but development of morphine tolerance in assays of pain-depressed behavior has not been studied. This study compared morphine antinociceptive tolerance in parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response in one group of rats and to depress operant responding for electrical brain stimulation (intracranial self-stimulation; ICSS) in another group of rats. Antinociception produced by morphine (1.0 mg/kg) was determined after a regimen of chronic treatment with either saline or morphine in separate subgroups of rats in each procedure. In rats receiving chronic saline, acid alone stimulated a stretching response and depressed ICSS, and both acid effects were blocked by 1.0 mg/kg morphine. Rats receiving chronic morphine displayed hyperalgesic responses to the acid noxious stimulus in both procedures. Complete tolerance developed to morphine antinociception in the assay of acid-stimulated stretching, but morphine retained full antinociceptive effectiveness in the assay of acid-depressed ICSS. These results suggest that morphine antinociception in an assay of pain-depressed behavior is relatively resistant to tolerance. More broadly, these results suggest that antinociceptive tolerance can develop at different rates or to different degrees for different measures of antinociception.

Keywords: Analgesia; Antinociception; Intracranial self-stimulation; Morphine; Tolerance.

Fig. 1

Effects of different acute treatments on stretching (A) and ICSS (B) in rats treated chronically with vehicle (open bars) or morphine (filled bars). A) Abscissa: acute treatment of 1.0 mg/kg morphine or vehicle + 1.8% lactic acid or vehicle. Ordinate: number of stretches during 30-min observation period. Two-way ANOVA showed that there was a significant main effect of acute treatment [F=45.4; P<0.001], significant main effect of chronic group [F=34.1; P<0.001], and significant treatment × chronic group interaction [F=9.7; P<0.001]. B) Abscissa: acute treatment of 1.0 mg/kg morphine or vehicle + 1.8% lactic acid or vehicle. Ordinate: percent baseline number of stimulations per component. Two-way ANOVA showed that there was a significant main effect of acute treatment [F=11.8; P<0.001], no significant main effect of chronic group [F=1.2; P=0.281], and no significant treatment × chronic group interaction [F=1.6; P=0.214]. * Asterisks indicate treatments that were significantly different from vehicle + vehicle within the same group. $ Dollar signs indicate a significant antinociceptive effect of morphine relative to the Veh+LA treatment within the same group. # Number signs indicate significance between chronic vehicle and chronic morphine groups after the same acute treatment.

Fig. 2

Effects of different acute treatments on ICSS frequency-rate curves in rats treated chronically with chronic vehicle (A) or chronic morphine (B). Abscissae: Frequency of electrical brain stimulation in Hz (log scale). Ordinates: ICSS rate expressed as percent maximum control rate (%MCR). ANOVA results were as follows: Chronic vehicle: Significant main effect of frequency [F(9,54)=184.5; P<0.001], no significant main effect of treatment [F(3,18)=3.1; P=0.055], but significant treatment × frequency interaction [F(27,126)=2.4; P<0.001]. Repeated morphine: Significant main effect of frequency [F(9,45)=142.9; P<0.001], significant main effect of treatment [F(3,15)=22.8; P<0.001], and significant treatment × frequency interaction [F(27,135)=5.8; P<0.001]. Filled points show frequencies at which a treatment produced effects significantly different from vehicle + vehicle.