Gabapentinoids (gabapentin and pregabalin), ligands of the alpha-2-delta subunit of voltage-gated calcium channels, and certain antidepressants such as tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are First-line drugs for the treatment of neuropathic pain and fibromyalgia.
These two types of drugs inhibit chronic pain by acting on the descending noradrenergic system from the locus coeruleus (LC) to the dorsal horn of the spinal cord. Gabapentinoids activate the LC while antidepressants inhibit norepinephrine reuptake in the synaptic cleft; The result in both cases is increased levels of norepinephrine in the spinal cord.
| Descending noradrenergic inhibition system (SIND) from the LC |
All noradrenergic nuclei of the central nervous system (CNS) are located in the brainstem and are classified as A1 to A7; the LC (A6) is the largest and has more than 50% of all noradrenergic neurons. LC neurons project to almost the entire CNS and modulate cognitive function (attention and memory), sleep and wakefulness, anxiety, and pain.
Several studies suggested that SIND from the ventral LC decreases spinal pain transmission. Broad multipolar neurons of the LC that project to the dorsal horn of the spinal cord play a decisive role in endogenous analgesia.
Under physiological conditions, norepinephrine released by descending noradrenergic axons exerts antinociceptive effects in the spinal dorsal horn through stimulation of alpha-2 adrenergic receptors (AR2A) coupled to inhibitory G proteins (Gi/o).
Activation of presynaptic RA2As in afferent pathways is associated with inhibition of voltage-modulated calcium channels; The result is less spinal release of excitatory neurotransmitters. Activation of postsynaptic RA2A produces the opening of rectifying K+ channels and thus reduces neuronal excitability. All these mechanisms participate in the SIND.
In animal models, SIND was found to be effective against thermal and dynamic hypersensitivity, in the early stages of neuropathic pain following neuronal damage, as a consequence of increased brain-derived neurotrophic factor (BDNF). ) in the dorsal horn of the spinal cord.
Noradrenaline released in the spinal cord stimulates cholinergic interneurons that release acetylcholine, which is essential to attenuate the hypersensitivity effect of spinal norepinephrine after nerve damage. SIND is essential for endogenous analgesia and represents the target of numerous drugs used in the treatment of neuropathic pain. Therefore, activation of the LC is associated with the release of norepinephrine and with the excitation of cholinergic interneurons in the spinal cord.
| Chronic neuropathic pain |
In the context of chronic neuropathic pain, noradrenergic neurons in the LC are less responsive to noxious stimuli, such that endogenous analgesia is compromised, particularly with respect to abnormal astroglial glutamate regulation.
Glutamate is a primary regulator of excitation of noradrenergic neurons by acting on AMPA receptors. In the CNS, there are two types of glutamate transporters in astroglia that regulate extracellular glutamate: glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter.
In rats with chronic hypersensitivity, peripheral nerve damage is related to reduced GLT-1 expression, through activation of histone deacetylases (HDACs), and increased basal extracellular glutamate concentrations. and less release of it. Likewise, patients with established neuropathic pain have a reduced capacity for descending physiological inhibition of pain.
Gabapentinoids
Gabapentin is an anticonvulsant also associated with analgesic effects in neuropathic pain and interacts with the alpha-2-delta subunit of voltage-modulated calcium channels that regulate the release of excitatory amino acids in the medulla.
SIND plays an important role in the analgesia associated with gabapentin. Depletion or blockade of noradrenergic signaling in the spinal cord of mice following peripheral nerve injury abolishes the analgesic effect of gabapentin.
The drug acts similarly in humans; Oral administration of the dose that produces postsurgical analgesia is accompanied by an increase in the concentration of norepinephrine in the cerebrospinal fluid of patients with joint pain who will undergo orthopedic surgery.
Taken together, the data suggest that SIND plays a critical role in the analgesic efficacy of gabapentin.
Although the drug does not exert direct effects on GABA receptors or spinal GABA release, it modifies GABA release in the brain differentially depending on the brain region.
In rodents with early neuropathic pain, 2 to 3 weeks after peripheral nerve damage, gabapentin-induced analgesia and activation of LC neurons are suppressed by blockade of AMPA glutamate receptors. Furthermore, the drug not only reduces the influence of GABA in the LC, it also induces the release of glutamate in the LC, with the activation of the SIND.
In rats, 2 to 3 weeks after peripheral nerve damage, selective blockade of GLT-1 in the LC abolishes the effects of gabapentin on glutamate levels and hypersensitivity. Therefore, GLT-1-mediated glutamate release in astrocytes would be essential for the analgesic effects of gabapentin.
The results together suggest that the drug inhibits the presynaptic release of GABA and induces the release of glutamate in the astrocytes of the LC, thereby increasing the neuronal activity of the LC and the SIND, at least in the early stages of neuropathic pain.
However, unlike what has been observed in animal models, gabapentin often does not completely relieve neuropathic pain in humans, probably because GLT-1 expression in the LC decreases by about 80% at 8 weeks after neuronal damage occurs (experimental studies are carried out within 3 to 4 weeks following peripheral nerve injury).
Valproic acid inhibits HDAC action and increases the decreased expression of GLT-1 in the LC. In the future, it will be interesting to determine whether the administration of valproic acid is associated with recovery from gabapentin-induced analgesia and with additive benefits in terms of relief of chronic neuropathic pain refractory to exclusive treatment with this agent.
| Antidepressants |
Chronic pain generates anxiety, a depressive state and increased perception of pain. However, the analgesic effects of antidepressants do not depend on the primary action of these drugs, since they also relieve pain in patients without depression. Furthermore, analgesic effects occur rapidly (within about a week), while antidepressant efficacy is observed 2 to 4 weeks after starting treatment.
Antidepressants act essentially through the modulation of norepinephrine and serotonin (5-HT) transporters. Inhibition of the reuptake of these neurotransmitters is associated with an increase in 5-HT levels in the CNS synaptic cleft. The analgesic efficacy of the different drugs is compared with the “number needed to treat”, that is, the number of patients in whom the treatment reduces pain by at least 50%.
The lower the NNT, the greater the effectiveness of the drug. In patients with painful polyneuropathy, the NNT of norepinephrine reuptake inhibitors (nortriptyline, desipramine) is 2.5, while that of SNRIs is 5, and that of selective serotonin inhibitors (SSRIs) is 6.8. . Thus, norepinephrine reuptake inhibition plays a more important role than 5-HT in the effects of antidepressants for the relief of neuropathic pain.
Animal studies showed that increased norepinephrine levels in the spinal dorsal horn participate in the inhibition of neuropathic pain associated with antidepressant use. In rats, intraperitoneal administration of duloxetine, an SNRI, inhibits hypersensitivity for about 4 hours, but the effect disappears by about 24 hours.
Hypersensitivity gradually decreases with repeated administration of duloxetine and returns to normal values after treatment for 3 consecutive days. The inhibitory effect of duloxetine is suppressed by intrathecal injection of RA2A antagonists. Likewise, intraperitoneal administration of amitriptyline, a TCA, for several days in a row slowly suppresses hypersensitivity after peripheral nerve injury, an action that is reversed by intrathecal injection of RA2A antagonists. The information taken together indicates that the main mechanism of action of antidepressants, in relieving neuropathic pain, is the increase of norepinephrine in the spinal cord.
The LC is characterized by presenting tonic and phasic neuronal activity; the latter is excitatory and appears shortly after the release of excitatory amino acids, essentially glutamate in the LC. In rats, noxious stimuli stimulate phasic activity of the LC, thereby inducing bilateral release of norepinephrine through projections to the dorsal horn of the spinal cord.
In experimental animals, spinal norepinephrine levels increase with the injection of capsaicin, which compromises noxious stimulus-induced analgesia (NAI). The pain associated with capsaicin injection induces phasic activation of LC, with release of norepinephrine in the spinal cord, involved in antinociceptive effects through RA2A.
In animal models of neuropathic pain, 6 weeks after nerve injury, AIEN is no longer observed and norepinephrine levels are no longer increased in the spinal cord. When tonic activity of the LC increases as a consequence of peripheral nerve damage, phasic reactivity to the noxious stimulus disappears. The involvement of AIEN in animals is recovered with the administration of duloxetine and amitriptyline for several days.
Chronic administration of antidepressants is associated with increased expression of BDNF messenger RNA in the rat hippocampus and in astrocyte culture; the effect is eliminated by the application of BDNF receptor antagonists. Thus, compromised LC function following peripheral nerve damage can be attenuated with the use of antidepressants by increasing BDNF levels.
| Strategies for addressing neuropathic pain |
The optimal strategy for the relief of neuropathic pain has not been precisely defined. Animal studies showed that gabapentinoids stimulate LC and activate SIND. Antidepressants increase norepinephrine levels in the spinal cord and are involved in the recovery of LC reactivity after nerve damage.
In this context, gabapentinoids would be more useful for early relief of neuropathic pain; When treatment is not effective, they can be replaced by antidepressants or combined treatment may be indicated. In late neuropathic pain, however, valproic acid (an HDAC inhibitor) could be added.
| Conclusions |
Gabapentinoids and antidepressants use SIND for the inhibition of chronic pain, including neuropathic pain. Gabapentinoids activate the LC by inhibiting GABA release and inducing glutamate release, thereby increasing norepinephrine levels in the spinal cord. Antidepressants increase the concentration of norepinephrine in the spinal cord by suppressing its reuptake.
The accumulation of norepinephrine inhibits chronic pain by acting on RA2A. However, SIND function is compromised in the chronic neuropathic pain state; antidepressants and HDAC inhibitors could restore the activity of this system. The findings together suggest that SIND recovery could be an important mechanism for the treatment of chronic pain.
SIIC- Ibero-American Society of Scientific Information
