Developmental responses to opioids reveals a lack of effect on stress‐induced corticosterone levels in neonatal rats

Abstract

1 The neonate has an unusual capacity for survival and the possibility exists that mechanisms for controlling stress responses may differ in the developing animal. In adults both endogenous and exogenous opioids can modulate the corticosterone responses to stress. We have studied this effect in neonatal rats and found that opioid modulation is absent in early postnatal development.2 Neonatal rats ofeither sex were injected with morphine (5-50mg kg-'), fentanyl (10-100 .tLg kg-'), buprenorphine (O.1-30 mg kg') or naloxone (O.1-Omg kg-') and plasma corticosterone measured fluorimetrically 15 or 20 min later. In addition naloxone reversibility studies (1 mg kg-', co-administered) were carried out for the opioid agonists. 3 In adult rats, elevations in plasma corticosterone caused by injection stress were potentiated by morphine, fentanyl and buprenorphine. In neonates, though injection stress-induced rises in plasma corticosterone were absent at 10 days, elevations were observed at 21 days and later. However, significant potentiation of this corticosterone response by fentanyl was absent at 21 days and at later ages (30 and 40 days) for morphine and buprenorphine. The potentiating effect of all three agonists did not become fully effective until day 45. In addition, in animals acclimatized to injection stress by 7 day injection pretreatment, fentanyl did not significantly alter corticosterone levels in 30 day old neonates.4 High doses ofnaloxone (10mg kg-')significantly increased the corticosterone response to injection stress in adult rats but this effect was absent in 30 day old animals. A dose of naloxone (I mg kg-') which had no significant effect on the corticosterone response inhibited the effects of morphine, fentanyl and buprenorphine in 45 day old and adult rats. 5 This late development of opioid action is unusual in comparison with the maturation of endogenous peptides, receptors and antinociceptive responses and suggests that alternative mechanisms may be involved in stress-control in the neonate.

The adolescent brain and age-related behavioral manifestations

“…Rodent studies have shown significant stressinduced activation of the HPA axis in neonatal rat pups, although sensitivity to stressors is reduced considerably after the first several postnatal days, with this stress hyporesponsive period (SHRP) lasting for most of the first 2 weeks of postnatal life [481]. While similar peak corticosterone responses to stressors have occasionally been observed in weanlings, adolescent and adult rats [23,82,202], stress-induced HPA activation has more consistently been reported to increase ontogenetically following the SHRP in rats to reach an asymptote around adolescence, at least in males [29,357,452,463,569,574]. In recent work using mice, however, adolescents were observed to have lower corticosterone levels than adults following the mild stress of saline injection [312].…”

“…In this regard, it may be highly significant that several studies have incidentally noted that adolescent rats exhibit lower drug-induced increases in plasma corticosterone levels than do their more mature counterparts. This paradoxically attenuated corticosterone response to drug exposure has been seen in adolescent rats following challenge with morphine [29], cocaine [313] as well as ethanol [497], and in adolescent mice following amphetamine [312]. To the extent that elevations in corticosterone contribute to the reward value of drugs, higher levels of adolescent drug exposure may be necessary to attain the reinforcing value that these drugs have in more mature individuals.…”

“…Furthermore, given evidence that corticosterone contributes to the rewarding value of drugs [199,201], earlier discussed findings that adolescent rodents exhibit lower drug-induced increases in plasma corticosterone than adults [29,312,313,497] may likewise be of relevance. Rats during adolescence also exhibit numerous age-specific peculiarities in the way they respond to reward contingencies, showing delayed extinction in an aversive task [378], but more rapid extinction and reduced partial reinforcement extinction effects for appetitive reinforcers (e.g., [56]).…”

“…This notion implies, however, that reward values would be progressively increased with increasing elevations in corticosterone levels, which may not be the case-at least in studies conducted in adult animals (where increases beyond a threshold level of corticosterone necessary to support drug self-administration may not necessarily lead to greater drug intake; [201]). Thus, it remains to be determined whether adolescent attenuations in drug-induced corticosterone release reported in laboratory animals [29,312,313,497] contribute to the high per occasion level of use of alcohol [33,346] and potentially other drugs [270] seen in human adolescents relative to their more mature counterparts.…”

Contexts and Consequences

“…For example, reminiscent of human adolescent behavior, adolescent rats are often hyperactive and explore more vigorously relative to rats of other ages (Spear et al, 1980). In addition, both human adolescents and adolescent laboratory rats show an enhanced hormonal and physiological response to stressors (Bailey and Kitchen, 1987;Meaney et al, 1985;Ramaley and Olson, 1974;Rivier, 1989;Walker et al, 1986Walker et al, , 1998. What makes these similarities interesting in the present context is other research that suggests that exploratory behavior and stress may be important factors involved in the tendency of human adolescents to drink heavily (Baer et al, 1987;Deykin et al, 1987;Pohorecky, 1991;Tschann et al, 1994;Wills, 1986).…”