Introduction
The antinociceptive and/or analgesic effect of opioids is subjected to bidirectional modulation by a range of neuroactive nonopioid substances. In some cases the interaction between opioids and antiopioids is purely pharmacologic, whereas in other cases the interactions may have important physiologic significance. Antiopioids not only modulate antinociception induced by exogenously administered opioids but may also be involved in the development of opioid tolerance, dependence, and opioid insensitivity in neuropathic pain.
Several types of interactions between opioids and nonopioids have been described: (1) Synergistic antinociception between opioids and nonopioids that have antinociceptive properties. The best described interaction is between spinally administered opioids and α-2 adrenoceptor agonists, which cause enhanced antinociception. (2) Potentiation of opioid-induced antinociception by other inhibitory substances that are not antinociceptive by themselves. (3) Antagonism of the effects of opioids by antiopioid endogenous peptides. (4) Opioid-induced increases in activation of N-methyl-D-aspartate (NMDA) receptors for glutamate, which curtail the effects of opioids.
The concept that there exist endogenous antiopioids has been suggested for some time (see Cesselin, 1995, for review). The original concept referred primarily to peptides, including cholecystokinin (CCK), FMRFamide-related peptides, and melanocyte inhibiting-factor (MIF)-related peptides (Faris et al., 1983; Kastin et al., 1984; Yang et al., 1985). Recent data suggest that endogenous antiopioids may also include glutamate acting on NMDA receptors (Mao et al., 1995a). In this chapter, we focus on the endogenous antiopioids and discuss the possible involvement of these systems in modulating opioid analgesia in normal and pathologic conditions.