The effects of laboratory handling procedures on naloxone-precipitated withdrawal behavior in morphine-dependent rats

Previous studies of opiate dependence in our laboratory have shown that opiate-naive (control) animals can display behaviors normally ascribed to withdrawal following naloxone challenge. The possibility arises that in these control rats, the stress of the induction of dependence, pharmacological challenge, and behavioral testing may result in the release of endogenous opioids such that on naloxone administration withdrawal behaviors are elicited. In the present study, we have utilized two differing experimental protocols for the induction of morphine dependence in rats that would represent the extremes of normal laboratory handling procedures and have then assessed withdrawal behaviors following naloxone challenge. In control animals, the results show that the stressors alone are insufficient to allow for the precipitation of naloxone-induced withdrawal. However, withdrawal behavior was generally greater in the opiate-dependent animals in the "high" rather than the "low" stress group, suggesting a summation of opiate effects. Similarly, a residual effect was noted in the control opiate-naive animals; naloxone rather than saline (control) challenged rats displayed a slightly higher incidence of withdrawal behavior. These results stress the importance of maintaining constant laboratory protocols, minimizing stressful procedures, and performing appropriate controls in assessing opiate dependence and withdrawal.