Effect of Motor Impairment on Analgesic Efficacy of Dopamine D2/3 Receptors in a Rat Model of Neuropathy

Abstract

Testing the clinical efficacy of drugs that also have important side effects on locomotion needs to be properly designed in order to avoid erroneous identification of positive effects when the evaluation depends on motor-related tests. One such example is the evaluation of analgesic role of drugs that act on dopaminergic receptors, since the pain perception tests used in animal models are based on motor responses that can also be compromised by the same substances. The apparent analgesic effect obtained by modulation of the dopaminergic system is still a highly disputed topic. There is a lack of acceptance of this effect in both preclinical and clinical settings, despite several studies showing that D2/3 agonists induce antinociception. Some authors raised the hypothesis that this antinociceptive effect is enhanced by dopamine-related changes in voluntary initiation of movement. However, the extent to which D2/3 modulation changes locomotion at analgesic effective doses is still an unresolved question. In the present work, we performed a detailed dose-dependent analysis of the changes that D2/3 systemic modulation have on voluntary locomotor activity and response to four separate tests of both thermal and mechanical pain sensitivity in adult rats. Using systemic administration of the dopamine D2/3 receptor agonist quinpirole, and of the D2/3 antagonist raclopride, we found that modulation of D2/3 receptors impairs locomotion and exploratory activity in a dose-dependent manner across the entire range of tested dosages. None of the drugs were able to consistently diminish either thermal or mechanical pain perception when administered at lower concentrations; on the other hand, the larger concentrations of raclopride (0.5-1.0 mg/kg) strongly abolished pain responses, and also caused severe motor impairment. Our results show that administration of both agonists and antagonists of dopaminergic D2/3 receptors affects sensorimotor behaviors, with the effect over locomotion and exploratory activity being stronger than the observed effect over pain responses.

Keywords: dopamine; pain; quinpirole; raclopride.

Figure 1

Locomotor activity. Effect of different doses of quinpirole (A, C) and raclopride (B, D) in distance traveled (A, B) and rearing activity (C, D) in the open-field arena. Black dots represent control animals (sham), and white dots represent animals with a peripheral nerve injury (SNI). Gray shaded area represents vehicle administration. Each point represents mean ± SEM. Statistical differences between saline injection and each drug concentration is separated per experimental group (RM two-way ANOVA followed by Bonferroni test: sham group, ^*P < 0.05, ^***P < 0.001; SNI group, ^#P < 0.05, ^##P < 0.01, ^###P < 0.001).

Figure 2

Effect of quinpirole in pain-related behavior. Effect of different doses of quinpirole in normal (sham) and neuropathic rats (SNI), submitted to nociceptive tests of mechanical and thermal painful stimulation. Paw withdrawal thresholds of the left hind paw in the Von Frey test (A) and in paw pressure test (B). Thermal thresholds measured by radiant heat response applied to the tail (C) and to the hind paw (D). Gray shaded area represents vehicle administration. Each point represents mean ± SEM. Statistical differences between saline injection and each drug concentration is separated per experimental group (RM two-way ANOVA followed by Bonferroni test: sham group, ^*P < 0.05).

Figure 3

Effect of raclopride in pain-related behavior. Effect of different doses of raclopride in normal (sham) and neuropathic rats (SNI), submitted to nociceptive tests of mechanical and thermal painful stimulation. Paw withdrawal thresholds of the left hind paw in the Von Frey test (A) and in paw pressure test (B). Thermal thresholds measured by radiant heat response applied to the tail (C) and to the hind paw (D). Gray shaded area represents vehicle administration. Each point represents mean ± SEM. Statistical differences between saline injection and each drug concentration is separated per experimental group (RM two-way ANOVA followed by Bonferroni test: sham group, ***P < 0.001; SNI group, ^#P < 0.05, ^##P < 0.01, ^###P < 0.001).