Attenuation of Acute Morphine Withdrawal in the Neonatal Rat by the Competitive NMDA Receptor Antagonist LY235959

Abstract

The present study examined the ability of LY235959, a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, to attenuate behaviors and c-fos mRNA expression associated with acute morphine withdrawal in the infant rat. Rat pups were given a single dose of morphine (10.0 mg/kg, s.c.) or saline. Two hours later, pups were removed from the dam and injected with either LY235959 (10.0 mg/kg, s.c.) In humans, exposure to opiates for either medical or nonmedical reasons leads to dramatic behavioral and neural changes resulting in physical dependence (Trujillo and Akil 1991b). Although physical dependence is classically thought to develop after chronic exposure to opiates (chronic opiate dependence), the adaptational changes underlying physical dependence begin with the first exposure to an opiate (Heishman et al. 1989a,b;Kirby et al. 1990). Thus, acute opiate withdrawal refers to the withdrawal syndrome precipitated by administration of an opioid antagonist after either a single dose or a short-term infusion of opioid agonist (Martin and Eades 1964;Bickel et al. 1988).Despite decades of research, our understanding of the mechanisms underlying opiate physical dependence and withdrawal is still very limited (Mayer et al. 1999;Trujillo 1999) and multiple mechanisms may operate in these processes (Thorat et al. 1994). There is increasing evidence indicating that N-methyl-D-aspartate (NMDA) receptor antagonists inhibit the development of mu receptor mediated opiate dependence in the adult NO . 3 rodent, and that the NMDA receptor and its second messenger systems play pivotal roles in opiate tolerance, dependence and withdrawal (Trujillo and Akil 1991a;Inturrisi 1997;Mao 1999;Mayer et al. 1999).It is not known whether these mechanisms in adults apply to infants. On the one hand, opiate dependence can be established in fetuses or infant rat pups if the dams are exposed to opiates during their pregnancy or the pups are treated directly with opiates Barr 1995, 2000;Windh et al. 1995;Barr et al. 1998). On the other hand, the neonatal CNS is both structurally and functionally different from that of the adult, and significant changes in opioid actions occur both prenatally and postnatally (Barr 1992(Barr , 1993Fitzgerald 1995;Marsh et al. 1997;Fitzgerald and Jennings 1999). More importantly, the NMDA receptor, which is believed to play a crucial role in the establishment of opiate dependence, undergoes qualitative and quantitative changes during development (Kalb et al. 1992;Hori and Kanda 1994;Kalb and Fox 1997). These include significant developmental alterations both in the density of the receptor (Tremblay et al. 1988;Morin et al. 1989;Represa et al. 1989), the sensitivity of the receptor complex to magnesium Bowe and Nadler 1990;Morrisett et al. 1990), and the rise and decay times of the NMDA receptor-mediated excitatory post-synaptic currents (EPSCs) (Akaike and Rhee 1997;Bardoni et al. 1998). Recently, due to the advancement in cloning technology and gene knockout technology, the molecular structure of the...

Distinct Profiles of Anxiety and Dysphoria during Spontaneous Withdrawal from Acute Morphine Exposure

“…We examined the effects of LY235959, a competitive NMDA receptor antagonist shown to attenuate precipitated morphine withdrawal (Jones et al , 2002), using doses (1-3 mg/kg) that prevent tolerance to morphine analgesia (Bilsky et al , 1996) and sensitization to morphine-induced locomotion (Mendez and Trujillo, 2008). LY235959 produced a dose-dependent attenuation of startle potentiation (Figure 4) [Morphine × LY235959 interaction: F 2,33 = 14.27, p < .001].…”

“…NMDA receptor antagonists also alleviate signs of opiate withdrawal (Harris et al , 2008; Kawasaki et al , 2005; Rasmussen, 1995). LY235959, a competitive NMDA receptor antagonist that reduces precipitated morphine withdrawal (Jones et al , 2002), produced a dose-dependent attenuation of startle potentiation. These results clearly indicate that startle elevation shares a pharmacological profile with other measures of opiate withdrawal.…”

Regional Fos expression induced by morphine withdrawal in the 7-day-old rat

“…Given that withdrawal can be precipitated by injections of antagonist in the same regions of the adult and infant brain, it appears that some of the neural circuitry, and perhaps some intracellular signaling paths, that mediate withdrawal in adult and infant are similar. Nonetheless there are differences that lie in the ability of chronic opiates, but not acute opiates, to engage mechanisms that include, but may not be limited to NMDA glutamate receptors (Jones et al, 2002; Zhu & Barr, 2000, 2001, 2003, 2004). Furthermore, although the use of an opiate antagonist is standard in the animal studies to understand mechanisms of withdrawal, in humans withdrawal is more gradual.…”

“…There are dramatic increases in levels of c-fos mRNA in the olfactory bulb and small increases in the hypothalamus and medulla of 7-day-old morphine dependent rats after naloxone-induced withdrawal (Maeda et al, 2002), but more regional specificity is not known. In addition, whole brain and spinal cord show changes in c-fos mRNA (Akbarian et al, 2002; Jones et al, 2002) in an acute opiate withdrawal model. These and other loci are also associated with withdrawal when microinjected with an opiate antagonist (Jones & Barr, 2001) and with conditioned place preference when microinjected with morphine (Barr & Rossi, 1992).…”

Changing Mechanisms of Opiate Tolerance and Withdrawal during Early Development: Animal Models of the Human Experience

“…Infant behaviors include increased ultrasonic vocalizations upon separation from the dam and littermates, head swaying, paw movement, and rolling (Table 1; Barr et al 1998; Jones and Barr 1995; Thornton and Smith 1997; Thornton et al 1997; Windh et al 1995). Administration of naloxone after a single opiate injection induces similar withdrawal signs (Jones et al 2002; Perez-Saad et al 1996). Some withdrawal behaviors also occur in the fetal rat after precipitated withdrawal when the dam has been treated with morphine (Ceger and Kuhn 2000; Jones and Barr 2000; Kirby 1981).…”