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.

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.

Diffuse noxious inhibitory controls (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 into the mechanisms involved in the regulation of DNIC. The most recent data suggest that DNIC may have a dual outcome encompassing not only analgesic 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 validate 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.

Chronic pain is a widespread condition responsible for a huge socioeconomic negative impact. Several monoaminergic systems, such as the noradrenergic system, are involved in descending modulation of pain (DMP) events, either through noxious stimuli facilitation or inhibition. Even though this is known, the pharmacologic approaches to treat severe chronic joint inflammatory pain (CJIP) are still mostly unsuccessful. To study the changes on descending noradrenergic pain modulation caused by CJIP, we performed spinal pharmacological studies, evaluated the expression levels of dopamine β-hydroxylase (DBH), the noradrenaline biosynthetic enzyme, and of the α2-adrenoreceptor (AR), and quantified the noradrenaline (NE) levels at the spinal cord of monoarthritic (MA) animals. MA was induced in adult male Wistar rats by complete Freund’s adjuvant injection (CFA) in the tibiotarsal joint. Control animals were injected with CFA vehicle. Movement-induced allodynia (ankle-bend test), mechanical hyperalgesia (Randall Selitto test) and signs of inflammation (inflammation score) were weekly evaluated in all animals during 6 weeks post-intraarticular injection. For the pharmacological studies (week 5), an intrathecal catheter was implanted above the L4-L5 spinal segments and one week later (week 6) cumulative doses (1, 5, 10µg) of clonidine, an α2-AR agonist, or saline were injected through the catheter. The effects of each dose were evaluated by the Randall Selitto test. DBH and α-2AR expression and NE levels were evaluated at L4 and 5 segments by immunohistochemistry and HPLC, respectively. MA animals showed typical movement-induced allodynia and mechanical hyperalgesia during the 6 weeks when compared to controls. Clonidine induced anti-hyperalgesia in MA animals, more significant at the highest dose, and produced no effects in controls. On MA rats, DBH labeling was significantly increased, no differences were found in α2-AR expression and NE spinal levels were lower, in comparison to controls In conclusion, chronic MA causes a loss of NE spinal input, triggered by the ongoing nociceptive input. However, a compensatory antinociceptive noradrenergic spinal mechanism to counteract this condition appears to be also developing, as indicated by DBH increase. Therapeutic strategies aiming at strengthening these antinociceptive noradrenergic spinal effects could represent new avenues when treating CJIP.