Despite the existence of a large body of information on the subject, the me
chanisms of opiate tolerance and dependence are not yet fully understood. A
lthough the traditional mechanisms of receptor down-regulation and desensit
ization seem to play a role, they cannot entirely explain the phenomena of
tolerance and dependence. Therefore, other mechanisms, such as the presence
of antiopiate systems and the coupling of opiate receptors to alternative
G-proteins, should be considered. A further complication of studies of opia
te tolerance and dependence is the multiplicity of endogenous opiate recept
ors and peptides. This review will focus on the endogenous opioid system-pe
ptides, receptors, and coupling of receptors to intracellular signaling via
G-proteins-in the context of their roles in tolerance and dependence, Opio
id peptides include the recently discovered endomorphins and those encoded
by three known genes-pro-opiomelanocortin, pro-enkephalin, and pro-dynorphi
n. They bind to three types of receptors-mu, delta, and kappa. Each of the
receptor types is further divided into multiple subtypes. These receptors a
re widely known to be coupled to G-proteins of the G(i) and G(o) subtypes,
but an increasing body of results suggests coupling to other G-proteins, su
ch as G(s). The coupling of opiate receptors to G(s), in particular, has im
plications for tolerance and dependence. Alterations at the receptor and tr
ansduction level have been the focus of many studies of opiate tolerance an
d dependence. In these studies, both receptor down-regulation and desensiti
zation have been demonstrated in vivo and in vitro. Receptor down-regulatio
n has been more easily observed in vitro, especially in response to morphin
e, a phenomenon which suggests that some factor which is missing in vitro p
revents receptors from down-regulating in vivo and may play a critical role
in tolerance and dependence. We suggest that antiopiate peptides may opera
te in vivo in this capacity, and we outline the evidence for the antiopiate
properties of three peptides: neuropeptide FF, orphanin FQ/nociceptin, and
Tyr-W-MIF-1. In addition, we provide new results suggesting that Tyr-W-MIF
-1 may act as an antiopiate at the cellular level by inhibiting basal G-pro
tein activation, in contrast to the activation of G-proteins by opiate agon
ists. Elsevier Science Inc.