Search Results (8)

Diffuse noxious inhibitory control (DNIC), also known as conditioned pain modulation (CPM) in humans, is a paradigm wherein the heterotopic application of a noxious stimulus results in the attenuation of another spatially distant noxious input. The pre-clinical and clinical studies show the involvement of several neurochemical systems in DNIC/CPM and point to a major contribution of the noradrenergic, serotonergic, and opioidergic systems. Here, we thoroughly review the latest data on the monoaminergic and opioidergic studies, focusing particularly on pre-clinical models of chronic pain. We also conduct an in-depth analysis of these systems by integrating the available data with the descending pain modulatory circuits and the neurochemical systems therein to bring light to the mechanisms involved in the regulation of DNIC. The most recent data suggest that DNIC may have a dual outcome encompassing not only analgesic effects but also hyperalgesic effects. This duality might be explained by the underlying circuitry and the receptor subtypes involved therein. Acknowledging this duality might contribute to validating the prognostic nature of the paradigm. Additionally, DNIC/CPM may serve as a robust paradigm with predictive value for guiding pain treatment through more effective targeting of descending pain modulation. Full article

The insular cortex is an important hub for sensory and emotional integration. It is one of the areas consistently found activated during pain. While the insular’s connections to the limbic system might play a role in the aversive and emotional component of pain, its connections to the descending pain system might be involved in pain intensity coding. Here, we used anterograde tracing with viral expression of mCherry fluorescent protein, to examine the connectivity of insular axons to different brainstem nuclei involved in the descending modulation of pain in detail. We found extensive connections to the main areas of descending pain control, namely, the periaqueductal gray (PAG) and the raphe magnus (RMg). In addition, we also identified an extensive insular connection to the parabrachial nucleus (PBN). Although not as extensive, we found a consistent axonal input from the insula to different noradrenergic nuclei, the locus coeruleus (LC), the subcoereuleus (SubCD) and the A5 nucleus. These connections emphasize a prominent relation of the insula with the descending pain modulatory system, which reveals an important role of the insula in pain processing through descending pathways. Full article

Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect of cancer treatment, often linked with pain complaints. Patients report mechanical and thermal hypersensitivity that may emerge during chemotherapy treatment and may persist after cancer remission. Whereas the latter situation disturbs the quality of life, life itself may be endangered by the appearance of CIPN during cancer treatment. The causes of CIPN have almost entirely been ascribed to the neurotoxicity of chemotherapeutic drugs in the peripheral nervous system. However, the central consequences of peripheral neuropathy are starting to be unraveled, namely in the supraspinal pain modulatory system. Based on our interests and experience in the field, we undertook a review of the brain-centered alterations that may underpin pain in CIPN. The changes in the descending pain modulation in CIPN models along with the functional and connectivity abnormalities in the brain of CIPN patients are analyzed. A translational analysis of preclinical findings about descending pain regulation during CIPN is reviewed considering the main neurochemical systems (serotoninergic and noradrenergic) targeted in CIPN management in patients, namely by antidepressants. In conclusion, this review highlights the importance of studying supraspinal areas involved in descending pain modulation to understand the pathophysiology of CIPN, which will probably allow a more personalized and effective CIPN treatment in the future. Full article

(1) Background: Noradrenaline and serotonin have modulatory roles in pain signaling and in exercise-induced hypoalgesia. Patients with chronic whiplash-associated disorders often show impaired exercise-induced hypoalgesia. Therefore, this study aimed to examine the isolated effect of activating serotonergic or noradrenergic descending pathways on hypoalgesia at rest and in response to exercise in patients with chronic WAD by using respectively a single dose of a selective serotonin reuptake inhibitor (SSRI) and a selective norepinephrine reuptake inhibitor (NRI). (2) Methods: Twenty-five people with chronic WAD participated in this double-blind randomized controlled crossover experiment. Serotonin and noradrenaline concentrations were modulated by the oral ingestion of a single dose of citalopram (i.e., SSRI) or atomoxetine (i.e., SNRI). Quantitative sensory testing (including pressure pain thresholds and conditioned pain modulation) was measured before and after exercise in combination with no medication (1), atomoxetine (2), or citalopram (3) at three different test days. (3) Results: Random-intercept linear mixed models analysis was used to analyze pain outcomes (i.e., pain at rest and exercise-induced hypoalgesia) before and after exercise over the three conditions in patients with chronic WAD. No differences in pain at rest were found between the three conditions before exercise. The effect of exercise on pain outcome measures was not influenced by medication intake. The occupational status of the participants had a significant influence on the effect of exercise and medication on pain outcomes (p < 0.05). Patients working full-time had some positive effect of atomoxetine on pain facilitation (p < 0.05). Unemployed patients had some negative effect of citalopram on pain tolerance and experienced exercise-induced hypoalgesia (p < 0.05). (4) Conclusions: A single dose of citalopram or atomoxetine did not result in changes in hypoalgesia at rest and in response to exercise. These results do not support the use of SSRI or selective NRI to overcome impaired hypoalgesia at rest or in response to exercise in people with chronic WAD. Effect of exercise and medication on pain in patients with chronic WAD is influenced by the occupational status. Full article

(1) Background: Dysregulation in serotonergic and noradrenergic systems may be implicated in the neurobiophysiological mechanisms underlying pain-related cognitive impairment in chronic whiplash-associated disorders (CWAD). This study aimed to unravel the role of serotonergic and noradrenergic descending pathways in cognitive functioning at rest and in response to exercise in people with CWAD. (2) Methods: 25 people with CWAD were included in this double-blind, randomized, controlled crossover study. Endogenous descending serotonergic and noradrenergic inhibitory mechanisms were modulated by using a single dose of a selective serotonin reuptake inhibitor (Citalopram) or a selective norepinephrine reuptake inhibitor (Atomoxetine). Cognitive performance was studied at rest and in response to exercise (1) without medication intake; (2) after intake of Citalopram; and (3) after intake of Atomoxetine. (3) Results: After Atomoxetine intake, selective attention improved compared with the no medication day (p < 0.05). In contrast, a single dose of Citalopram had no significant effect on cognitive functioning at rest. When performing pairwise comparisons, improvements in selective attention were found after exercise for the no medication condition (p < 0.05). In contrast, after intake of Citalopram or Atomoxetine, selective and sustained attention worsened after exercise. (4) Conclusions: A single dose of Atomoxetine improved selective attention only in one Stroop condition, and a single dose of Citalopram had no effect on cognitive functioning at rest in people with CWAD. Only without medication intake did selective attention improve in response to exercise, whereas both centrally acting medications worsened cognitive performance in response to a submaximal aerobic exercise bout in people with CWAD. Full article

Pain transmission at the spinal cord is modulated by noradrenaline (NA)-mediated actions that arise from supraspinal areas. We studied the locus coeruleus (LC) to evaluate the expression of the cathecolamine-synthetizing enzyme tyrosine hydroxylase (TH) and search for local oxidative stress and possible consequences in descending pain modulation in a model of hydrocephalus, a disease characterized by enlargement of the cerebral ventricular system usually due to the obstruction of cerebrospinal fluid flow. Four weeks after kaolin injection into the cisterna magna, immunodetection of the catecholamine-synthetizing enzymes TH and dopamine-β-hydroxylase (DBH) was performed in the LC and spinal cord. Colocalization of the oxidative stress marker 8-OHdG (8-hydroxyguanosine; 8-OHdG), with TH in the LC was performed. Formalin was injected in the hindpaw both for behavioral nociceptive evaluation and the immunodetection of Fos expression in the spinal cord. Hydrocephalic rats presented with a higher expression of TH at the LC, of TH and DBH at the spinal dorsal horn along with decreased nociceptive behavioral responses in the second (inflammatory) phase of the formalin test, and formalin-evoked Fos expression at the spinal dorsal horn. The expression of 8-OHdG was increased in the LC neurons, with higher co-localization in TH-immunoreactive neurons. Collectively, the results indicate increased noradrenergic expression at the LC during hydrocephalus. The strong oxidative stress damage at the LC neurons may lead to local neuroprotective-mediated increases in NA levels. The increased expression of catecholamine-synthetizing enzymes along with the decreased nociception-induced neuronal activation of dorsal horn neurons and behavioral pain signs may indicate that hydrocephalus is associated with alterations in descending pain modulation. Full article

Vincristine is a vinca alkaloid anti-mitotic drug with a broad spectrum of effects on solid and hematologic cancers. The major dose-limiting factor of this anti-cancer regimen is painful peripheral neuropathy. However, no gold-standard analgesic option has been used clinically. In this study, we investigated the effects and mechanism of bee venom acupuncture (BVA) to alleviate peripheral neuropathic pain induced by repeated intraperitoneal infusions of vincristine (1 mg/kg/day, days 1–5 and 8–12) in rats. Subcutaneous injection with bee venom (BV, 1.0 mg/kg) at the ST36 acupoint ameliorated cold and mechanical hypersensitivity (i.e., aberrant withdrawal responses in acetone drop and von Frey hair tests, respectively). In vivo extracellular recording demonstrated that BVA inhibited cutaneous cold (acetone) and mechanical (brush, press, and pinch) stimuli-elicited abnormal hyperexcitation of the spinal wide dynamic range (WDR) neurons in vincristine-treated rats. In addition, the microinjection of lidocaine into the ipsilateral locus coeruleus or the antagonism of the spinal α₂-adrenergic receptors clearly reversed the effects of BVA on cold and mechanical hypersensitivity, indicating a vital role of the descending noradrenergic modulation in analgesia. These findings suggest that BVA could be a potential therapeutic option for vincristine-induced peripheral neuropathy. Full article

The noradrenergic system is paramount for controlling pain and emotions. We aimed at understanding the descending noradrenergic modulatory mechanisms in joint inflammatory pain and its correlation with the diffuse noxious inhibitory controls (DNICs) and with the onset of anxiodepressive behaviours. In the complete Freund’s adjuvant rat model of Monoarthritis, nociceptive behaviors, DNICs, and anxiodepressive-like behaviors were evaluated. Spinal alpha2-adrenergic receptors (a2-AR), dopamine beta-hydroxylase (DBH), and noradrenaline were quantified concomitantly with a2-AR pharmacologic studies. The phosphorylated extracellular signal–regulated kinases 1 and 2 (pERK1/2) were quantified in the Locus coeruleus (LC), amygdala, and anterior cingulate cortex (ACC). DNIC was attenuated at 42 days of monoarthritis while present on days 7 and 28. On day 42, in contrast to day 28, noradrenaline was reduced and DBH labelling was increased. Moreover, spinal a2-AR were potentiated and no changes in a2-AR levels were observed. Additionally, at 42 days, the activation of ERKs1/2 was increased in the LC, ACC, and basolateral amygdala. This was accompanied by anxiety- and depressive-like behaviors, while at 28 days, only anxiety-like behaviors were observed. The data suggest DNIC is attenuated in prolonged chronic joint inflammatory pain, and this is accompanied by impairment of the descending noradrenergic modulation and anxiodepressive-like behaviors. Full article