The effects of repeated opioid administration on locomotor activity: II. Unidirectional cross-sensitization to cocaine

Abstract

Sensitization refers to an increase in sensitivity to the effects of a drug and is believed to play a role in the etiology of substance use disorders. Cross-sensitization has been observed between drugs from different pharmacological classes and may play a role in the escalation of drug use in polydrug-abusing populations. The purpose of this study was to examine cross-sensitization between opioids and cocaine and to determine the extent to which cross-sensitization is mediated by an opioid's selectivity for mu, kappa, and delta receptors. Separate groups of rats were treated with opioid receptor agonists and antagonists every other day for 10 days, and the locomotor effects of cocaine were tested 8 days later. The mu agonists, morphine and buprenorphine, and the delta agonist, BW373U86 [(+/-)-4-[(R(*))-[(2S(*),5R(*))-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide hydrochloride], produced cross-sensitization to cocaine, such that repeated administration of these drugs over a 10-day period significantly enhanced cocaine's locomotor effects when tested later. Coadministration of the opioid antagonist naltrexone prevented morphine and buprenorphine from producing cross-sensitization. Coadministration of naltrexone, but not the delta antagonist naltrindole, also prevented BW373U86 from producing cross-sensitization. The kappa agonist spiradoline failed to produce cross-sensitization, but coadministration of spiradoline prevented morphine and buprenorphine from producing cross-sensitization. The ability of spiradoline to block cross-sensitization was itself blocked by the kappa antagonist nor-binaltorphimine. The mixed mu/kappa opioids butorphanol, nalbuphine, and nalorphine did not produce cross-sensitization under any condition examined. These data indicate that agonist activity at mu receptors positively modulates cross-sensitization between opioids and cocaine, whereas agonist activity at kappa receptors negatively modulates this effect.

Fig. 1.

Effects of cumulative doses of cocaine in three groups of rats treated with saline and tested approximately 18 months apart (saline 1, saline 2, saline 3). Left, locomotor activity expressed as a percentage of saline control values. Right, AUC estimates for each group. Vertical lines, S.E.; where not indicated, the S.E. fell within the data point.

Fig. 2.

Effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 10 mg/kg cocaine (10 COC), 2.0 mg/kg d-amphetamine (2 AMP), and 2.0 mg/kg methamphetamine (2 MET). Left, locomotor activity expressed as a percentage of saline control values. Right, AUC estimates for each group. Horizontal lines, significant differences between groups (p < 0.05). Vertical lines, S.E.; where not indicated, the S.E. fell within the data point. Significant differences are indicated as follows: a, significantly different from saline control group (p < 0.05).

Fig. 3.

Top, effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 0.3 mg/kg naltrexone (0.3 NTX), and 3.0 mg/kg naltrexone (3.0 NTX). Bottom, effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 10 mg/kg nor-binaltorphimine (10 NBNI), and 1.0 mg/kg naltrindole (1.0 NTI). Left, locomotor activity expressed as a percentage of saline control values. Right, AUC estimates for each group. Vertical lines, S.E.; where not indicated, the S.E. fell within the data point.

Fig. 4.

Effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 3.0 mg/kg spiradoline (3.0 SPR), and 10 mg/kg spiradoline (10 SPR). Left, locomotor activity expressed as a percentage of saline control values. Right, AUC estimates for each group. Vertical lines represent the S.E.; where not indicated, the S.E. fell within the data point.

Fig. 5.

Top, effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 3.0 mg/kg morphine (3.0 MOR), 10 mg/kg morphine (10 MOR), and 10 mg/kg morphine + 0.3 mg/kg naltrexone (10 MOR + 0.3 NTX). Bottom, effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 0.3 mg/kg buprenorphine (0.3 BUP), 1.0 mg/kg buprenorphine (1.0 BUP), and 1.0 mg/kg buprenorphine + 0.3 mg/kg naltrexone (1.0 BUP + 0.3 NTX). Left, locomotor activity expressed as a percentage of saline control values. Right, AUC estimates for each group. Horizontal lines, significant differences between groups (p < 0.05). Vertical lines, S.E.; where not indicated, the S.E. fell within the data point. Significant differences are indicated as follows: a, significantly different from saline control group (p < 0.05); and b, significantly different from naltrexone-treated group (p < 0.05).

Fig. 6.

Effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 3.0 mg/kg BW373U86 (3.0 BW), 10 mg/kg BW373U86 (10 BW), 10 mg/kg BW373U86 + 1.0 mg/kg naltrindole (10 BW + 1.0 NTI), and 10 mg/kg BW373U86 + 0.3 mg/kg naltrexone (10 BW + 0.3 NTX). Left, locomotor activity expressed as a percentage of saline control values. Right, AUC estimates for each group. Horizontal lines, significant differences between groups (p < 0.05). Vertical lines, S.E.; where not indicated, the S.E. fell within the data point. Significant differences are indicated as follows: a, significantly different from saline control group (p < 0.05); and b, significantly different from naltrexone-treated group (p < 0.05).

Fig. 7.

Top, effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 10 mg/kg morphine (10 MOR; redrawn from Fig. 5), 10 mg/kg morphine + 10 mg/kg spiradoline (10 MOR + 10 SPR), and 10 mg/kg morphine + 10 mg/kg spiradoline + 10 mg/kg nor-binaltorphimine (10 MOR + 10 SPR + 10 NBNI). Bottom, effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 1.0 mg/kg buprenorphine (1.0 BUP; redrawn from Fig. 5), 1.0 mg/kg buprenorphine + 10 mg/kg spiradoline (1.0 BUP + 10 SPR), and 1.0 mg/kg buprenorphine + 10 mg/kg spiradoline + 10 mg/kg nor-binaltorphimine (1.0 BUP + 10 SPR + 10 NBNI). Left, locomotor activity expressed as a percentage of saline control values. Right, AUC estimates for each group. Horizontal lines, significant differences between groups (p < 0.05). Vertical lines, S.E.; where not indicated, the S.E. fell within the data point. Significant differences are indicated as follows: a, significantly different from saline control group (p < 0.05); and b, significantly different from spiradoline-treated group (p < 0.05).

Fig. 8.

Top, effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 3.0 mg/kg butorphanol (3.0 BUT), 10 mg/kg butorphanol (10 BUT), 10 mg/kg butorphanol + 10 mg/kg nor-binaltorphimine (10 BUT + 10 NBNI), 30 mg/kg butorphanol (30 BUT; right only), and 30 mg/kg butorphanol + 10 mg/kg nor-binaltorphimine (30 BUT + 10 NBNI; right only). Middle, effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 3.0 mg/kg nalbuphine (3.0 NALB), 10 mg/kg nalbuphine (10 NALB), 10 mg/kg nalbuphine + 10 mg/kg nor-binaltorphimine (10 NALB + 10 NBNI), 30 mg/kg nalbuphine (30 NALB; right only), and 30 mg/kg nalbuphine + 10 mg/kg nor-binaltorphimine (30 NALB + 10 NBNI; right only). Bottom, effects of cumulative doses of cocaine in separate groups of rats treated with saline (saline), 3.0 mg/kg nalorphine (3.0 NALR), 10 mg/kg nalorphine (10 NALR), 10 mg/kg nalorphine + 10 mg/kg nor-binaltorphimine (10 NALR + 10 NBNI), 30 mg/kg nalorphine (30 NALR; right only), and 30 mg/kg nalorphine + 10 mg/kg nor-binaltorphimine (30 NALR + 10 NBNI; right only). Left, locomotor activity expressed as a percentage of saline control values. Right, AUC estimates for each group. Vertical lines, S.E.; where not indicated, the S.E. fell within the data point.