Ethanol attenuation of morphine dependence: comparison to dizocilpine

Abstract

Recent studies indicate that morphine dependence, assessed as the severity of naloxone-precipitated opiate withdrawal in rats, is attenuated by dizocipline, a non-competitive, excitatory amino acid antagonist. Because ethanol is a putative excitatory amino acid antagonist, the present study compared the effects of co-administration of ethanol to that of dizocilpine on morphine dependence. Rats were administered morphine (10 mg/kg) twice daily for 9 days. One group received ethanol (1 g/kg) co-administration, another received dizocilpine (0.05 mg/kg) co-administration, and a third served as vehicle controls. On day 10, all rats received naloxone (4 mg/kg) injections and ratings of several classic signs of opiate withdrawal were made. Both ethanol- and dizocilpine-treated rats showed significantly less severe precipitated opiate withdrawal overall, with the ethanol group showing reduced ratings of some specific signs. These results demonstrate that ethanol, like dizocilpine, attenuates the development of morphine dependence. The results are consistent with the action of ethanol at glutamate receptors.

Glutamatergic Neurotransmission in Alcoholism

“…NMDA antagonists can block ethanol withdrawal seizures [36,63,88]. Ethanol can attenuate the development of morphine dependence as the NMDA antagonist MK-801 [118]. The effects are consistent with the action of ethanol at NMDA receptor.…”

Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast)

“…A weeklong AV411 (vs. vehicle) treatment was delayed until 12 days after the start of the opioid regimen to allow dependence to develop prior to AV411 administration. This delay was included to test whether AV411 could be effective after morphine dependence was established, as prior literature documents other drugs that fail to affect withdrawal if drug treatment begins after the establishment of opioid dependence (Shoemaker et al, 1997; Trujillo, 2000). AV411 administered after the establishment of morphine dependence significantly protected rats from both morphine and oxycodone spontaneous withdrawal-induced weight loss that occurred following removal of drug pumps (Figure 3).…”

“…In addition, the experiment was designed to test whether AV411 could be effective when treatment began after morphine dependence was established; that is, several days of morphine dosing preceded the start of AV411. This is an important question as the literature supports that some treatments can suppress opioid withdrawal only when drug treatment begins prior to the establishment of dependence, but cannot affect withdrawal if begun after dependence exists (Shoemaker et al, 1997; Trujillo, 2000). …”