Precipitated and conditioned withdrawal in morphine-treated rats

Abstract

Rationale: Stimuli that are paired with opioid withdrawal can themselves produce effects similar to withdrawal that might promote relapse.

Objective: This study compared precipitated and conditioned withdrawal and tested whether withdrawal is modified by clonidine or morphine.

Methods: Morphine-treated rats (10 mg/kg/12 h) received naloxone (3.2 mg/kg) in a novel environment (conditioned stimuli [CS]). Other rats received naloxone in the absence of the CS. Body weight and observable signs were used to measure withdrawal.

Results: Naloxone produced weight loss and withdrawal signs in morphine-treated rats. Following pairings of the CS and naloxone, the CS alone had effects similar to naloxone; conditioned withdrawal was greater after three naloxone/CS pairings, as compared to one, and with longer morphine treatment. Antagonist-precipitated withdrawal was greater in rats that previously were physically dependent on morphine, as compared to withdrawal in rats that were never dependent; however, conditioned withdrawal did not differ between groups. When administered concurrently with naloxone, clonidine (0.1 mg/kg) attenuated some precipitated withdrawal signs, although conditioned withdrawal was largely unchanged. Administration of 10 mg/kg of morphine before the CS alone attenuated all conditioned withdrawal signs, whereas 0.1 mg/kg of clonidine before the CS alone reduced some directly observable signs and not weight loss.

Conclusions: Conditioned withdrawal occurs rapidly and is greater with longer periods of morphine treatment or more pairings of naloxone and the CS; however, a history of physical dependence does not increase conditioned withdrawal. Modification of conditioned withdrawal by drugs might be a useful approach for treating relapse.

Figure 1

Effect of number of conditioning trials and length of morphine treatment on precipitated or conditioned withdrawal. Ordinates: top panels, change in body weight (g) that occurred during the 30 min session; bottom 4 rows, frequency of directly observable signs. Abscissa: PW = precipitated withdrawal (the only [Group 2] or last of 3 [Groups 1 and 3] conditioning session when naloxone [Groups 2 and 3] or saline [Group 1] was administered prior to placement in the CS environment; Conditioned Withdrawal Test Day. * = P<0.05 for paired versus unpaired groups (Groups 1 versus 2, 1 versus 3, and 4 versus 5).

Figure 2

Effects of prior morphine treatment and physical dependence on precipitated and conditioned withdrawal. Data from Groups 1 and 3 are replotted on this figure. Ordinates: top panels, change in body weight (g) that occurred during the 30 min session; bottom 4 rows, frequency of directly observable signs. * = P<0.05 for no prior dependence versus prior dependence (Groups 3 versus 6). See Figure 1 for other details.

Figure 3

Effects of clonidine treatment on the establishment of conditioned withdrawal. Data from Groups 4 and 5 are replotted in this figure (circles and squares). Ordinates: top row, change in body weight (g) that occurred during the 30 min session; bottom 4 rows, frequency of directly observable signs. * = P<0.05 for naloxone only versus naloxone plus clonidine (Groups 5 versus 7). See Figure 1 for other details.

Figure 4

Effects of morphine and clonidine on established conditioned withdrawal. Ordinates: top row, change in body weight (g) that occurred during the 30 min session; bottom 4 rows, frequency of directly observable signs. * = P<0.05 for saline versus morphine and saline versus clonidine (Groups 5 versus 8 and 5 versus 9). Filled symbols denote session preceded by a single injection of morphine (filled, inverted triangles) or clonidine (filled diamonds). See Figure 1 for other details.