Monoamine regulation of pain

(A) Descending pain inhibition from the PAG can be initiated by electrical stimulation or direct microinjection of opioids. Recent evidence also indicates a role for COX inhibitors in the PAG as well. Opioids and cannabinoids inhibit pain by enhancing the baseline firing rate of off-cells and eliminating the off-cell pause in response to nociceptive stimuli. Inhibition of on-cell activity may abolish enhanced pain states. The on-cells and off-cells might correlate with pain facilitatory (+) and inhibitory (–) neurons in the RVM, respectively. At the level of the spinal cord, opioids can inhibit transmitter release from primary afferent terminals as well as activity of pain transmission neurons. Norepinephrine (NE) release from spinopetal noradrenergic fibers from medullary sites also inhibits pain transmission. Tricyclic antidepressants (TCAs) and other norepinephrine reuptake inhibitors enhance the antinociceptive effect of opioids by increasing the availability of spinal norepinephrine (box). Areas labeled “i–iii” in the small diagram correspond with labeled details of the larger diagram. α2A, α2-adrenergic receptor; DRG, dorsal root ganglion; SNRI, serotonin/norepinephrine reuptake inhibitor; SP, substance P. (B) Mice deficient in dopamine β-hydroxylase that do not produce norepinephrine show a diminished antinociceptive effect of morphine compared with control animals, suggesting that the presence of norepinephrine, presumably released in the spinal cord, is required for the full expression of morphine antinociception. The dashed line represents the 50% effect, and the corresponding dose is the ED50 (that is the dose producing a 50% effect). % MPE, percentage maximal possible effect. ***P < 0.001 compared with the control group. Error bars represent SEM. Copyright National Academy of Sciences, USA (151).

In healthy controls, the noradrenergic system has only a minor role in regulation of the pain system. Following plastic changes induced by injury or inflammation, the contribution of the noradrenergic system in pain control is increased. For example, it has been reported that following peripheral injury, noradrenaline acting on cutaneous α1-adrenoceptors aggravates pain, while selective activation of cutaneous, perineural, or intra-articular α2-adrenoceptors attenuates pain. Following injury, the central noradrenergic system contributes to feedback inhibition of pain, predominantly due to action on the spinal α2-adrenoceptors. Promotion of the antinociceptive action of the noradrenergic system with drugs acting on the α2-adrenoceptor alone or as an adjuvant has proved effective in treating a number of pain conditions. For example, an α2-adrenoceptor agonist applied topically has reduced neuropathic pain (Davis et al., 1991), intra-articular administration has reduced postoperative pain after knee surgery (Gentili et al., 1996), and intrathecal administration has reduced pain in various types of conditions, including intractable cancer pain (Eisenach et al., 1995). Among side effects induced by α2-adrenoceptor agonists are sedation, bradycardia, and hypotension. Side-effects may be reduced by using local rather than systemic treatments, particularly when using α2-adrenoceptor agonists that due to their pharmacokinetic properties have a limited spread from the site of administration. With systemic administrations of α2-adrenoceptor agonists, the synergistic interaction with other anesthetic and/or analgesic compounds that have different side-effects allows using low doses that is expected to help in reducing undesired actions.

NA descending control

Overall summary