Further Studies of the Role of Opioid Receptors in the Nigra in the Morphine Withdrawal Syndrome

Bilateral injection of naloxone (3.0–30.0 nmol) into the substantia nigra of morphine -dependent rats produced a withdrawal syndrome consisting of wet-dog shakes, teeth chattering, irritability to touch, diarrhea and hypothermia . Intense wet-dog shakes and grooming were observed after intranigral injection of the mu selective antagonist d-Phe-Cys-Try-d-Trp-Orn-Thr-Pen-Thr-NH ₂ (CTOP, 3.0–30.0 nmol) in morphine-dependent animals. Body temperature after 30.0 nmol CTOP was significantly increased. A significant positive correlation between body temperature and wet-dog shakes was observed in morphine-dependent animals that received CTOP. Intranigral injection of β-funaltrexamine (β-FNA, 10.0 nmol), an irreversible mu antagonist, produced no signs of withdrawal in morphine -dependent animals. However, intranigrat injection of β-FNA (1.0–3.0 nmol) suppressed the antinociceptive effect of the mu-selective agonist, d-Ala ² , N -Me-Phe ⁴ ,Gly ⁵ -ol- enkephalin (DAGO, 1.0 nmol). The withdrawal syndrome produced by CTOP (10.0 nmol) was not suppressed by the administration of U50,488H (10.0 nmol), a kappa agonist, suggesting that the absence of an effect of β-FNA was not due to its kappa agonist activity. Neither the delta-selective antagonist, naltrindole (NTI, 10.0 nmol) nor the kappaselective antagonist, nor-binaltorphimine (nor-BNI, 10.0 nmol) produced withdrawal. Only wet-dog shakes were observed when CTOP, NTI and nor-BNI (5 nmol each) were administered together into the nigra. These studies suggest an involvement of mu receptors in the nigra in the wet-dog shakes and thennoregulatory dysfunction that occur during withdrawal of morphine. However, the subtypes ofopioid receptors in the nigra, that mediate the other signs of morphine withdrawal remain obscure.