Antinociceptive interactions between Mu-opioid receptor agonists and the serotonin uptake inhibitor clomipramine in rhesus monkeys: role of Mu agonist efficacy

Abstract

Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine < morphine < methadone). Clomipramine and each mu agonist were studied alone and in fixed-proportion mixtures in assays of schedule-controlled responding, thermal nociception, and capsaicin-induced thermal allodynia. In the assay of schedule-controlled responding, all mu agonists dose-dependently decreased response rates. Clomipramine was inactive alone and did not alter the effects of mu agonists. In the assay of thermal nociception, all mu agonists produced dose-dependent antinociception. Clomipramine was inactive alone but produced a proportion-dependent enhancement of the antinociceptive effects of nalbuphine > morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.

Fig. 1.

Effects of nalbuphine (Nalbu; left), morphine (Morph; center), and methadone (Meth; right) alone or in combination with different proportions of clomipramine (Clomip) in the assay of schedule-controlled responding. Abscissae: dose of mu agonist alone or in the mixture in mg/kg (log scale). The corresponding dose of clomipramine depended on the proportion of clomipramine in the mixture. Ordinates: percentage control rates of responding. Each point shows mean ± S.E.M. for three monkeys.

Fig. 2.

Effects of nalbuphine (Nalbu; left), morphine (Morph; center), and methadone (Meth; right) alone or in combination with different proportions of clomipramine (Clomip) in the assay of thermal nociception at 50 (top) and 54°C (bottom). Abscissae: dose of mu agonist alone or in the mixture in mg/kg (log scale). The corresponding dose of clomipramine depended on the proportion of clomipramine in the mixture. Ordinates: %MPE. Each point shows mean ± S.E.M. for four monkeys. Open symbols represent significantly (p < 0.05) different from mu agonist alone within a given mu agonist dose. Note that one monkey was tested with a high dose of 10 mg/kg nalbuphine alone to achieve >50% MPE at 50°C, but because this was the only monkey tested at this dose, data from this test are excluded.

Fig. 3.

Effects of nalbuphine (Nalbu) alone or in combination with different proportions of clomipramine (Clomip) in the assay of capsaicin-induced thermal allodynia. Abscissa: dose of nalbuphine alone or in the mixture in mg/kg (log scale). The corresponding dose of clomipramine depended on the proportion of clomipramine in the mixture. Ordinate: %MPE. Each point shows mean ± S.E.M. for three monkeys. Open symbols represent significantly (p < 0.05) different from mu agonist alone within a given mu agonist dose.

Fig. 4.

Time course of antinociceptive effects from the low-efficacy mu agonist nalbuphine, the moderate-efficacy mu agonist morphine, the high-efficacy mu agonist methadone, the serotonin uptake inhibitor clomipramine, and saline administration in different groups of rhesus monkeys. Abscissa: time (min) after administration. Ordinate: %MPE at the 50°C thermal intensity. Each point represents mean ± S.E.M. of three rhesus monkeys. Two-way repeated-measures analysis of variance revealed a significant main effect of time (F_6,12 = 12.8; p < 0.05), drug (F_4,8 = 39.1; p < 0.05), and a significant time × drug interaction (F_24,48 = 9.2; p < 0.05). Post hoc analysis using the Bonferroni method for multiple planned comparisons demonstrated that nalbuphine and methadone were significantly different (p < 0.05) from vehicle at 3 min, and all mu agonists were significantly different from vehicle at 10 to 30 min. Nalbuphine's effects returned to vehicle levels at 56 min and methadone levels at 300 min. Morphine's effects were still significant at 300 min. Open symbols represent significantly (p < 0.05) different vehicle within a given time point.