Studies of direct excitatory effects elicited by opioid agonists on various types of neurone have been confirmed and expanded in numerous laboratories following the initial findings reviewed previously by Stanley Crain and Ke-Fei Shen. However, the critical role of the endogenous glycolipid GM1 ganglioside in regulating Gs-coupled, excitatory opioid receptor functions has not been addressed in any of the recent reviews of opioid stimulatory mechanisms. This article by Stanley Crain and Ke-Fei Shen focuses on crucial evidence that the concentration of GM1 in neurones might, indeed, play a significant role in the modulation of opioid receptor-mediated analgesia, tolerance and dependence.