Co-administration of nalbuphine attenuates the morphine-induced anxiety and dopaminergic alterations in morphine-withdrawn rats

• Published in: Psychopharmacology Vol. 238; no. 4; pp. 1193 - 1211
• Main Authors: Raghav, Rahul, Jain, Raka, Jacob, Tony G., Dhawan, Anju, Roy, Tara S.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2021; Springer; Springer Nature B.V
• Subjects: Addictions; Analgesics, Opioid - pharmacology; Animals; Anxiety; Anxiety - chemically induced; Anxiety - psychology; Biomedical and Life Sciences; Biomedicine; Chronic effects; Complications and side effects; Cyclic AMP; Cyclic AMP - metabolism; Diagnosis; Dopamine - metabolism; Dopamine receptors; Dopaminergic mechanisms; Dosage and administration; Dose-Response Relationship, Drug; Drug dependence; Drug withdrawal symptoms; Male; Mesolimbic system; Morphine; Morphine - pharmacology; Motor Activity - drug effects; Nalbuphine; Nalbuphine - pharmacology; Naloxone; Narcotic-Related Disorders - psychology; Narcotics; Neurosciences; Opioid receptors; Original Investigation; Pharmacology/Toxicology; Physiological aspects; Psychiatry; Rats; Rats, Wistar; Substance Withdrawal Syndrome - psychology; Transcription; Tyrosine 3-Monooxygenase - metabolism; Withdrawal; India; Co-administration; Morphine; Anxiety; Naloxone; Dopamine; Nalbuphine
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-021-05765-3

Introduction The classical effects of exogenous opioids, such as morphine, are predominantly mediated through μ-opioid receptors. The chronic use of morphine induces anxiety-like behavior causing functional changes in the mesolimbic dopaminergic system. The mixed μ/κ-agonist, nalbuphine, used either as an analgesic or as an adjuvant with morphine, produces different and opposite effects. However, whether nalbuphine can be used to antagonize morphine-induced anxiety and dopaminergic alterations is not fully known. Objective This study aimed to compare acute and chronic effects of nalbuphine on morphine-induced anxiety and dopaminergic alterations in rats. Methods Male adult Wistar albino rats were made opioid-dependent by administering increasing doses of morphine (5–25 mg/kg; i.p.; b.i.d.). Withdrawal was induced by naloxone (1 mg/kg, i.p.), 4 h after the last morphine injection. Anxiety-like behavior was measured using Activity Monitor (Coulbourn Instruments, Inc. USA). Thereafter, the animals were sacrificed and the brain dissected out and the level of cAMP and the transcriptional and translational expression of TH was measured. Nalbuphine was co-administered with morphine, acutely and chronically, at various doses (0.1, 0.3, 1.0, 3.0 mg/kg, i.p.). Results Morphine-dependent rats showed a significant higher anxiety and cAMP levels and a significant decrease in the expression of TH. Co-administration of chronic doses of nalbuphine attenuates the higher anxiety, cAMP levels, and upregulates the TH expressions; however, the acute nalbuphine treatment does not attenuate the morphine-induced side effects. Conclusion Therefore, nalbuphine might have an important role in attenuating the anxiety and the effects of the dopaminergic pathway and may have potential in the treatment of opioid addiction.