In summary, dysfunctions in pain modulation systems exist in individuals with and without chronic pain, and importantly, these deficits may be improved with drugs modulating the dysfunctional pain modulatory system, especially in individuals with less efficient CPM initially, highlighting the implication of CPM enhancement in pain management.Multiple neurotransmitters, including monoamines and opioids, are involved in the modulation of pain by endogenous descending inhibitory pathway.
Monoamines: Serotonin, Noradrenaline and Dopamine
Endogenous descending pain inhibitory systems originating in midbrain and brainstem regions (e.g., PAG and NRM) rich in amino biogenic transmitters, including serotonin and norepinephrine, are activated by bulbospinal monoaminergic pathways that project onto the spinal cord. Clinical doses of adrenergic agonists (e.g., dexmedetomidine and phenylephrine) in rats inhibit DNIC, suggesting an involvement of adrenergic neurons in DNIC. Catecholamines like norepinephrine and epinephrine signal through the α2-adrenergic receptors concentrated in the spinal cord to produce an inhibitory effect. Noradrenergic-mediated inhibitory system act on descending pain modulatory circuits, including the RVM and PAG. Neurons of the dorsal horn in the spinal cord are directly inhibited by serotonin (from serotoninergic neurons). Serotonin, acting on facilitatory spinal 5-HT3 receptors, influences the expression of CPM.
A growing body of literature support the role of dopaminergic neurotransmission in the modulation of pain, however, the underlying mechanisms remain elusive. In healthy subjects, CPM effect was significantly more important following apomorphine, a non-specific dopamine agonist, than placebo administration (27% versus 4%, respectively). Inversely, the inhibition of dopaminergic neurotransmission in healthy human subjects using acute phenylalanine and tyrosine depletion (APTD) induced decreases of cerebral dopaminergic activity accompanied by increases of pain unpleasantness but not pain intensity. Even though parts of the descending pain inhibitory system involve dopaminergic pathways, no dysregulations in CPM contribute to altered pain processing in Parkinson’s disease (PD), a pathology mainly characterized by lower secretion of dopamine. However, the akinetic-rigid subtype of PD is associated, at a trend level, to impairment of pain inhibition.
Some patients with chronic pain conditions such as fibromyalgia, display reduced CPM efficacy as well as lower concentration of serotonin and noradrenaline in the cerebrospinal fluid. A recent study found a relationship between the efficacy of descending pain inhibition and basal monoamine levels in blood, specifically blood-bound norepinephrine and metanephrine concentrations. Patients with chronic pain and deficits in CPM presented lower peripherally (plasma) acting norepinephrine and metanephrine concentrations. Lower CPM-mediated pain inhibition of the RIII reflex has also been linked to a polymorphism in the serotonin transporter (5-HTT) gene (SLC6A4), but this association is not observed in all samples.
Pharmacological treatments engaging descending noradrenergic and serotonergic control pathways have shown some efficacy in the treatment of pain, demonstrating the importance of serotonin and norepinephrine in pain modulation. Antidepressants such as tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors are used for pain management in chronic pain conditions such as neuropathic pain, migraines, and fibromyalgia. Duloxetine, a serotonin–norepinephrine reuptake inhibitor (SNRI), benefited more patients with painful diabetic polyneuropathy and deficient CPM than subjects with efficient CPM. Furthermore, drug efficacy correlated with improvement in CPM efficacy.
The functioning of descending controls induced by counter-irritation include the analgesic action of endogenous opioid release, including enkephalins, B-endorphin, and dynorphins. Opioid receptors are contained on several primary afferents terminations in the dorsal horn of the spinal cord, in particular the PAG and probably also the rostro-ventral gray matter of the bulb. Dorsal horn neurons mediated by serotonergic neurons act on interneurons that contain enkephalins which limit the discharge transmitted from the primary afferents to the cells of the dorsal horn. In rats, plasticity of spinal serotonergic neurotransmission can modulate spinal mu-opioid receptors mechanisms.
In humans, pain inhibition and decrease in the nociceptive reflex induced by CPM can be completely blocked by naloxone hydrochloride, a non-selective and competitive opioid receptor antagonist after 5 min from the administration. These findings led Willer et al. (1990) to believe the supraspinal CPM phenomenon involves an opioidergic system. Similarly, the endogenous pain inhibitory systems activated by spatial summation is mediated by an opioid pathway. Basal mu-opioid receptor availability in the amygdala predicts pain-related brain activity (on the P260 component of somatosensory evoked potentials reflecting activity in the ACC) during CPM but does not affect the nociceptive reflex. The authors argue that the inhibition of pain-related brain activity induced by activation of mu-opioid receptors in the amygdala may depend on a cerebral mechanism different from descending modulation. King et al. (2013) further reported only a partial blockage of the CPM effect by naltrexone, a long-term opioid antagonist, highlighting the importance of endogenous opioid release in the expression of CPM with the effects of naltrexone being moderated by levels of pain catastrophizing.
In healthy individuals, the mu-opioid receptor agonist morphine impairs CPM expression, while tapentadol, a combined mu-opioid receptor agonist and noradrenaline reuptake inhibitor, does not affect CPM. Conversely, tapentadol enhances pain inhibition in chronic pain patients with diabetic polyneuropathy. In patients with chronic fatigue syndrome/fibromyalgia and rheumatoid arthritis, morphine produced anti-hyperalgesia effects (comparable to placebo), but neither morphine nor naloxone influenced CPM. Findings suggest that the opioid system might not be responsible for impaired endogenous pain inhibition by CPM in these patients. Repeated use of opioids in the course of chronic pain treatment may lead to decreased capacity for endogenous analgesia. Patients with chronic pain using oral opioids express smaller pain inhibition than patients with chronic pain using other analgesic. Moreover, the dosage and duration of opioid treatment correlate negatively with CPM efficacy. The finding that CPM is affected by opioid use might hint at mechanisms of pain modulation and opioid-induced hyperalgesia phenomenon.
In producing antinociception, the neural circuitry activated by endogenous opioids and cannabinoids overlap. Evidence of an implication of endogenous cannabinoids (endocannabinoids) in inhibitory pain modulation arises primarily from animal studies. In the rat, the endogenous descending pain-modulatory pathways that includes PAG, its projection to downstream RVM neurons, and their inhibitory projections to the dorsal horn of the spinal cord play an important role in cannabinoid modulation of spinal nociceptive processing by actions primarily at the cannabinoid receptors type 1 (CB1).
Cannabinoid receptor activation by endocannabinoids regulate the mode and the probability of g-aminobutyric acid (GABA) release within the midbrain PAG and modulate GABA release in the RVM neurons. Endocannabinoid signaling to CB1 and CB2 receptors in adult RVM is altered in persistent inflammation. Data suggest that cannabinoids produce antinociception in the superficial dorsal horn, in part, also by modulating descending noradrenergic systems. CB1 receptors on GABAergic neurons are involved in the electroacupuncture effect on DNIC function in a mouse model of knee osteoarthritis (Yuan et al., 2018). The spinal endocannabinoid anandamide (AEA) reduces neuropathic pain via CB1 or transient receptor potential vanilloid 1 (TRPV1) receptors, depending on its local concentration. Several ventrolateral PAG neurons co-express TRPV1 and CB1 receptors to produce antinociception. Some of the therapeutic action of the pain treatment metamizole or the triptans for migraines may act via endocannabinoid containing neurons and CB1 receptors in the lateral – ventrolateral PAG.