Depolarization of primary afferent sensory neurons of sufficient intensity leads to action potential production and signal generation in secondary and, ultimately, tertiary neurons. Synaptic transmission is regulated by the actions of both local inhibitory interneurons and efferent projections from the brainstem. The major inhibitory neurotransmitters relevant to this discussion are opioid peptides, norepinephrine, serotonin (5-HT), and endogenous cannabinoids.
In response to tissue damage and inflammation resident immune cells release endogenous opioids and opioid receptors are up-regulated on peripheral sensory fibers.21-23 Opioid receptor activation in primary afferent neurons inhibits depolarization; in the trigeminal-dorsal root complex it inhibits the release of glutamate; in the mid-brain it increases descending inhibitory activity; and in the brain it alters mood, produces sedation, and modulates the emotional response to pain.
Efferent projections from the brainstem to the spinal cord release norepinephrine and serotonin 5-HT. Activation of α2-adrenergic Gi-protein-coupled receptors by norepinephrine, which are expressed both presynaptically and postsynaptically, reduces both presynaptic and postsynaptic neuronal excitation. Similarly, activation of serotonergic Gi-protein-coupled receptors, which are also expressed both presynaptically and postsynaptically, exerts an inhibitory neuronal effect.
Nociceptive activity in sensory neurons, the spinal cord, and the periaqueductal grey can be inhibited by endogenous cannabinoids (2-arachidonylglycerol and anandamide).24,25 There are two G-protein-coupled cannabinoid (CB) receptors. CB1 receptors are expressed in sensory neurons, the spinal cord, and the brain. CB2 receptors are primarily expressed in immune cells; but in association with pain they may be upregulated in the trigeminal-dorsal root complex and in the central nervous system (CNS).26
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