Morphine Dependence and Dopaminergic Activity: Tests of Circling Responses in Rats With Unilateral Nigral Lesions

Abstract

I Rats with unilateral electrolytic lesions involving both parts of the substantia nigra show doserelated, ipsilateral circling responses to apomorphine which are stable over time. 2 In non-tolerant rats, morphine (up to 10 mg/kg) does not elicit any circling behaviour but as tolerance develops to morphine, initially 10 mg/kg daily and then 100 mg/kg daily for about 4 months, the rats show a progressive tendency to walk more towards the side of the lesion. This behaviour is qualitatively different from apomorphine-induced circling. 3 When apomorphine (0 to 1.0 mg/kg) and morphine (10 or 100 mg/kg) are tested together, the total amounts of 'circling' are increased in an additive manner. However, after 22 h withdrawal from morphine there is a more marked increase in apomorphine-induced circling which is related to the level of dependence. 4 It is suggested that the sensitivity of striatal dopamine receptors is not altered by morphine dependence and that the increased response to apomorphine in abstinence probably reflects changes in the modulating actions of other neurotransmitter systems in the striatum.

Dopamine Supersensitivity: A Novel Hypothesis of Opioid-Induced Neurobiological Mechanisms Underlying Opioid-Stimulant Co-use and Opioid Relapse

“…Evidence suggests that rats with 6-OHDA lesions will elicit ipsilateral turning behavior in response to opioid agonists but not antagonists and that this behavior can be blocked by naloxone; these data support the notion that opioids confer dopaminergic effects and suggest this assay is useful for detecting opioid-induced changes in behavior (72, 95,96). Consistent with the aforementioned evidence, 6-OHDA-related turning behavior is not evident when a single acute opioid dose is examined; it only emerges following chronic opioid exposure and then increases in frequency as opioid tolerance develops (96). In addition, once animals have developed a physical dependence on opioids, naloxone administration produces contralateral (e.g., antagonistic) turning behavior (72) which can be reversed by provision of the stimulant D2 agonists apomorphine and d-amphetamine (95).…”

“…In animals that have received a unilateral striatal lesion, dopaminergic agonism and antagonism produces ipsilateral and contralateral turning behaviors, respectively (94). Evidence suggests that rats with 6-OHDA lesions will elicit ipsilateral turning behavior in response to opioid agonists but not antagonists and that this behavior can be blocked by naloxone; these data support the notion that opioids confer dopaminergic effects and suggest this assay is useful for detecting opioid-induced changes in behavior (72, 95,96). Consistent with the aforementioned evidence, 6-OHDA-related turning behavior is not evident when a single acute opioid dose is examined; it only emerges following chronic opioid exposure and then increases in frequency as opioid tolerance develops (96).…”

“…Co-administration of apomorphine and morphine in non-tolerant rats has also been found to increase ipsilateral (e.g., agonist) circling behaviors in an additive manner, signifying a dopamine agonist effect. Moreover, once an animal that has developed opioid physical dependence has been withdrawn from opioids, morphine will no longer elicit a turning response; however, apomorphine will continue to elicit the ipsilateral (e.g., agonist) turning response in animals during a period of withdrawal, and the intensity of the turning behavior has been found to increase as a function of time since last opioid exposure (96).…”