Pharmacology and mechanisms of opioid analgesic activity

Opiates by an action at specific receptors can induce a highly selective alteration in the response of humans and animals to strong and otherwise aversive chemical, mechanical or thermal stimuli. Specific investigations in a variety of species from rodent to primate using microinjection techniques to examine the pharmacology of local drug action have shown potent antinociceptive actions to be mediated by a receptor specific action at a number of sites within the brain, including the periaqueductal gray (PAG: mu receptor), the rostral ventral medulla (mu/delta receptor) and the substantia nigra (mu receptor) and within the spinal dorsal horn (mu/delta/kappa receptor). Mechanistic studies have shown these actions in the different sites to be mediated by several discrete mechanisms. For example, in the PAG, the local opiate effect is likely mediated by the indirect activation of bulbospinal pathways, rostral projections to forebrain sites and by a local alteration in afferent input into the brainstem core. In the spinal cord, this effect is mediated by an action presynaptic to the primary afferent and by a post-synaptic effect to hyperpolarize projection neurons. In addition, it is now appreciated that mu and kappa receptors in the periphery can modulate the sensitized state of the small afferent terminal innervating inflamed tissue and exert an anti-hyperalgesic action. After systemic delivery of an opiate, it is thus clear that a wide array of central and peripheral systems serve to explain the powerful analgesic effect exerted by this class of agents.