Monoaminergic and Opioidergic Modulation of Brainstem Circuits: New Insights Into the Clinical Challenges of Pain Treatment?

Abstract

The treatment of neuropathic pain remains a clinical challenge. Analgesic drugs and antidepressants are frequently ineffective, and opioids may induce side effects, including hyperalgesia. Recent results on brainstem pain modulatory circuits may explain those clinical challenges. The dual action of noradrenergic (NA) modulation was demonstrated in animal models of neuropathic pain. Besides the well-established antinociception due to spinal effects, the NA system may induce pronociception by directly acting on brainstem pain modulatory circuits, namely, at the locus coeruleus (LC) and medullary dorsal reticular nucleus (DRt). The serotoninergic system also has a dual action depending on the targeted spinal receptor, with an exacerbated activity of the excitatory 5-hydroxytryptamine 3 (5-HT3) receptors in neuropathic pain models. Opioids are involved in the modulation of descending modulatory circuits. During neuropathic pain, the opioidergic modulation of brainstem pain control areas is altered, with the release of enhanced local opioids along with reduced expression and desensitization of μ-opioid receptors (MOR). In the DRt, the installation of neuropathic pain increases the levels of enkephalins (ENKs) and induces desensitization of MOR, which may enhance descending facilitation (DF) from the DRt and impact the efficacy of exogenous opioids. On the whole, the data discussed in this review indicate the high plasticity of brainstem pain control circuits involving monoaminergic and opioidergic control. The data from studies of these neurochemical systems in neuropathic models indicate the importance of designing drugs that target multiple neurochemical systems, namely, maximizing the antinociceptive effects of antidepressants that inhibit the reuptake of serotonin and noradrenaline and preventing desensitization and tolerance of MOR at the brainstem.

A Glitch in the Matrix: The Role of Extracellular Matrix Remodeling in Opioid Use Disorder

“…Opioids lead to long-lasting changes in gene transcription, protein signaling, receptor activity, synaptic morphology and plasticity, as well as neural circuit function that contribute to the development of addiction ( Hearing, 2019 ; Li et al, 2019 ; Madayag et al, 2019 ; Song et al, 2019 ; Valentinova et al, 2019 ; Koob, 2020 ; Jiang et al, 2021 ; Seney et al, 2021 ; Tavares et al, 2021 ; Trieu et al, 2022 ; Xue et al, 2022 ). A major class of signaling proteins involved in opioid-induced neural plasticity, include cell adhesion molecules (CAMs), matrix metalloproteinases (MMPs), and proteoglycans, and these proteins provide structural support to neurons, astrocytes, microglia in the formation of the extracellular matrix (ECM) and perineuronal nets (PNNs).…”

Knowing the Enemy Is Halfway towards Victory: A Scoping Review on Opioid-Induced Hyperalgesia

“…This may reflect the specific pain-masking effect of opioid substances, with associated cognitive conditioning coursing with subjective attribution of smaller importance to nociceptive inputs [ 11 , 42 ]. On the other hand, it’s important to note that opioids also modulate cognitive and affective/emotional brain processes, by affecting several key areas, including the amygdala, anterior cingulate gyrus, prefrontal cortex, thalami, and several brainstem nuclei [ 17 , 43 , 44 ]. An imaging study in patients with chronic pain showed reduced MOR availability associated with decreased pain-evoked activity in many of these areas [ 45 ] ( Table 1 ).…”

“…Opioids together with GABA and the monoamines serotonin and noradrenaline represent the main neurotransmitters involved in the modulation of nociceptive transmission from the primary sensory neurons, whose cell bodies are located within the dorsal root ganglia (DRG), to spinal dorsal horn neurons travelling to the brain. Opioids and GABA are released locally, by spinal interneurons, as well as by descending fibers originated in the brainstem, that also release serotonin and noradrenaline [ 44 ]. The most well characterized descending systems arise from the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway, the locus coeruleus (LC) and the dorsal reticular nucleus (DRt) [ 44 ].…”

Alterations in pain processing circuitries in episodic migraine

“…In individuals with chronic pain, it has been suggested that there is a shift in pain-modulation system functioning, such that it favors pro-nociception [ 59 ]. Indeed the persistence of pain may be attributable to mechanisms including a serotonergic modulatory system in which the RVM is involved in the maintenance as opposed to the establishment of chronic pain [ 60 ]. An important RVM mediated serotonergic role for bidirectional pain modulation has been established, and pro-nociception is likely facilitated by excitatory action of serotonin receptors at the spinal cord [ 59 , 61 ].…”