Endorphin System

The locus ceruleus and the A5 and A7 noradrenergic cell groups of the posterolateral pons are the main source of noradrenergic input to the dorsal horn. These regions send bilateral projections that primarily descend to contralateral laminae I, II, and V of the spinal dorsal horn, exerting an antinociceptive effect. The PAG sends input to the locus ceruleus and the A7 region. RVM neurons containing substance P or enkephalin also send input to A7. Consequently, the posterolateral pontine tegmentum provides a corresponding pathway for the PAG and RVM to provide descending nociception control over the spinal dorsal horn. Posterolateral pontine systems may also provide cortical control of spinal pain transmission. The anterior insular cortex has locus coeruleus and RVM connections, suggesting that inhibition of the insular outflow disinhibits noradrenergic neurons of the locus ceruleus.

NEUROCHEMICAL FOUNDATIONS OF DESCENDING PAIN MODULATION

Opioids have long been considered the archetypical analgesics, with endogenous opioids (“enkephalins”) believed to play a pivotal role in the modulation of pain transmission. Recently, however, it has been shown that the monoaminergic pathways mediate modulation of nociceptive processing. Monoaminergic systems include serotonergic, noradrenergic, and dopaminergic neurons that elicit either antinociceptive or pronociceptive effects, depending on the type of receptor involved and its location. Monoaminergic modulation entails complex interplay between primary nociceptive afferents, dorsal horn projection neurons, local interneurons, and glial cells.

The RVM is the major source of serotonergic input to the dorsal horn; it is the final common output for descending influences from rostral brain regions projecting to the superficial and deep dorsal horn. The PAG-RVM serotonergic pathway is considered to be the major endogenous pain modulatory system and the main target of supraspinal opioid analgesia. Serotonergic neurons can exert antinociceptive action (in response to chemical stimuli and neurogenic inflammation) as well as pronociceptive action (in response to mechanical stimuli), depending on the activation of different serotonergic receptors.

Noradrenergic neurons originating from locus ceruleus and A5 and A7 pontine tegmentum groups provide inhibition of nociceptive input via presynaptic alpha-2 receptors. In this case, noradrenergic modulation relies upon volume transmission, in contrast to the serotonergic system mediating punctate synaptic transmission. The effect of this noradrenergic system is essentially an extrasynaptic spread of neuroactive substances that may be involved in late and long-lasting changes of a group of neurons. The analgesic effects mediated through presynaptic alpha-2 receptors involve presynaptic inhibition in primary afferents, postsynaptic inhibition of projection neurons, as well as a complex interplay with opioid and adenosine antinociceptive systems.

Dopaminergic pathways originate mainly from A11 neurons of the periventricular posterior thalamus. Their activation results in diminished response to noxious stimuli mediated by D2 receptors, with concomitant inhibition of neurotransmitter release from primary afferents. Possibly, endogenous opioids provide potentiating effects that develop from. Conversely, D1 receptor activation engenders facilitated nociception transmission, both directly and by opioid antagonism. The possible mechanism of action for dopamine may rely on local dopamine concentration; low levels activate antinociceptive D2 receptors, and high levels elicit pronociceptive effects via D1 receptors.

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