The Effects of Morphine, Baclofen, and Buspirone Alone and in Combination on Schedule-Controlled Responding and Hot Plate Antinociception in Rats

Abstract

Better therapeutic options are needed for pain. Baclofen, buspirone, and morphine are characterized as having analgesic properties. However, little is known about potential interactions between analgesic effects of these drugs when combined. Furthermore, it is not known if the magnitude of these potential interactions will be similar for all drug effects. Thus, we tested the effects of these drugs alone and in combination for their capacity to produce thermal antinociception and to decrease food-maintained responding. Four male and four female Sprague-Dawley rats responded for food under a fixed-ratio 10 schedule; afterward they were immediately placed on a 52°C hot plate. Morphine, baclofen, and buspirone were examined alone and in 1:1 combinations, based upon ED₅₀ values. Morphine and baclofen effects were evaluated with the opioid antagonist naltrexone and the GABA_B antagonist (3-Aminopropyl)(diethoxymethyl)phosphinic acid (CGP35348), respectively. Morphine, baclofen, and buspirone dose dependently decreased operant responding, with the calculated ED₅₀ values being 7.09, 3.42, and 0.57 mg/kg, respectively. The respective antinociception ED₅₀ values were 16.15, 8.75, and 2.20 mg/kg. Analysis of 1:1 combinations showed the effects of morphine plus baclofen to decrease schedule-controlled responding and to produce thermal antinociception were synergistic. Effects of morphine plus buspirone and baclofen plus buspirone to decrease schedule-controlled responding were additive. Effects of the two combinations to produce thermal antinociception were synergistic. Naltrexone and CGP35348 antagonized the effects of morphine and baclofen, respectively. Synergistic antinociceptive effects, in conjunction with additive effects on food-maintained responding, highlight the therapeutic utility of opioid and non-opioid drug combinations.

Fig. 1.

Systemic baclofen and morphine decrease schedule-controlled responding for food and produce thermal antinociception. (A) Baclofen alone and in combination with equi-effective doses of morphine decreases schedule-controlled behavior. (B) Morphine alone and in combination with equi-effective doses of baclofen decreases schedule-controlled behavior. (C) Baclofen alone and in combination with morphine increases latency to respond to thermal stimulus. (D) Morphine alone and in combination with baclofen increases latency to respond to thermal stimulus. Ordinate in (A and C) depicts the rate of responding calculated as a percentage of control and in (B and D) the maximum percent effect (MPE) as a percentage of latency to respond to thermal stimulus. Abscissa depicts the dose of drug administered. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 vs. vehicle. Data reflect mean ± S.E.M., n = 8 rats/group.

Fig. 2.

Systemic buspirone and morphine decrease schedule-controlled responding for food and produce thermal antinociception. (A) Buspirone alone and in combination with equi-effective doses of morphine decreases schedule-controlled behavior in a dose-related manner. (B) Morphine alone and in combination with equi-effective doses of buspirone decreases schedule-controlled behavior. (C) Buspirone alone and in combination with morphine increases latency to respond to thermal stimulus. (D) Morphine alone and in combination with buspirone increases latency to respond to thermal stimulus. Ordinate in (A and C) depicts the rate of responding calculated as a percentage of control and in (B and D) the maximum percent effect (MPE) as a percentage of latency to respond to thermal stimulus. Abscissa depicts the dose of drug administered. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 vs. vehicle. Morphine dose-response curves are the same as those shown in Fig. 1. Data reflect mean ± S.E.M., n = 8 rats/group.

Fig. 3.

Systemic baclofen and buspirone decrease schedule-controlled responding for food and produce thermal antinociception. (A) Baclofen alone and in combination with equi-effective doses of buspirone decrease schedule-controlled behavior. (B) Buspirone alone and in combination with equi-effective doses of baclofen decrease schedule-controlled behavior. (C) Baclofen alone and in combination with buspirone increased latency to respond to thermal stimulus in a dose-related manner. (D) Buspirone alone and in combination with baclofen increased latency to respond to thermal stimulus. Ordinate in (A and C) depicts the rate of responding calculated as a percentage of control and in (B and D) the maximum percent effect (MPE) as a percentage of latency to respond to thermal stimulus. Abscissa depicts the dose of drug administered. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 vs. vehicle. Baclofen and buspirone dose-response curves are the same as those shown in Figs. 1 and 2, respectively. Data reflect mean ± S.E.M., n = 8 rats/group.

Fig. 4.

Effects of pretreatment with naltrexone on drug-induced changes in food-maintained responding and thermal antinociception. Abscissae: drug dose (mg/kg, i.p.), log scale; ordinates: (A, C, and E) Percent control rates of food-maintained responding. (B, D, and F) Percent maximum possible effect in the hot plate test. (A and B) Dose-dependent effects of morphine; (C and D) equi-effective dose combinations of baclofen and morphine; and (E and F) equi-effective dose combinations of buspirone and morphine with pretreatment with naltrexone. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 vs. vehicle or naltrexone, respectively, according to pretreatment. Morphine dose-response curves are the same as those shown in Fig. 1. Data reflect mean ± S.E.M., n = 8 rats/group.

Fig. 5.

Effects of pretreatment with CGP35348 on drug-induced changes in food-maintained responding and thermal antinociception. Abscissae: drug dose (mg/kg, i.p.), log scale; ordinates: (A, C, and E) percent control rates of food-maintained responding. (B, D, and F) Percent maximum possible effect in the hot plate test. (A and B) Dose-dependent effects of buspirone; (C and D) equi-effective dose combinations of baclofen and morphine; and (E and F) equi-effective dose combinations of buspirone and baclofen with 320 mg/kg CGP35348 pretreatment. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 vs. vehicle or CGP35348, respectively according to pretreatment. The baclofen dose-response curves are the same as those shown in Fig. 1. Data reflect mean ± S.E.M., n = 7 to 8 rats/group (one rat was lost to attrition).