ABSTRACT
Opioids are major modulators in the nervous system. They modulate synaptic transmission in nociceptive (pain-sensing) pathways and inhibit the responses of dorsal horn neurons to noxious stimuli (Duggan, Hall, and Headley, 1976; LeBars et al., 1976; Duggan and Fleetwood-Walker, 1993; Yaksh, 1993). Due to their powerful analgesic effects, opioids are the important agents for treatment of severe acute pain. One of the characteristics of opioids that limits their therapeutic potential is the problem of tolerance, i.e. higher dose of opioids is needed to produce the same effect after neurons are exposed to opioids for a prolonged period of time (Cox, 1993). Aside from tolerance, there is increasing evidence that opioids play important roles in two other long term changes in the brain — hyperalgesia (an increase in neuronal activity following tissue injury) and long term potentiation (LTP) (the long lasting potentiation of synaptic transmission induced by repetitive stimulation to excitatory synapses, a model for learning and memory). Following inflammation or tissue injury, the synthesis and the expression of endogenous opioids such as dynorphin can increase up to several fold in the brain and in the spinal cord (Dubner and Ruda, 1992). Opioid receptors also up-or down-regulate in these cases (Stevens et ai, 1991; Millan, 1993). Recent studies of LTP suggest that opioids are released following high frequency stimulation of various pathways, modulate plastic changes in synaptic strength and affect the induction and expression of LTP in the hippocampus (Bramham, 1992; Wagner, Terman, and Charkin, 1993; Weisskopf, Zalutsky, and Nicell, 1993). To understand how opioids produce these phenomena, the cellular mechanisms of opioid actions have to be known.
