Intra‐accumbal dopaminergic system modulates the restraint stress‐induced antinociceptive behaviours in persistent inflammatory pain

Abstract

Background: Stress activates several neural pathways that inhibit pain sensation. Nucleus accumbens (NAc), as an important component of the mesolimbic dopaminergic system, has a major role in pain modulation and is differentially affected by stress. Based on the nature of stressors, the direction of this effect is controversial. We previously showed that forced swim stress-induced analgesia through activation of NAc dopamine receptors. In this study, we aimed to examine the role of dopamine receptors within the NAc in restraint stress (RS)-induced analgesia. Methods: Male Wistar rats weighing 230-250 g were unilaterally implanted with a cannula into the NAc. D1-like dopamine receptor antagonist, SCH-23390 (0.25, 1 and 4 µg/0.5 µL saline), or D2-like dopamine receptor antagonist, Sulpiride (0.25, 1 and 4µg/0.5µl DMSO), were microinjected into NAc in two separate super groups 5 min prior to exposure to RS. Their control groups just received intra-accumbal saline or DMSO (0.5 µl) respectively. The formalin test was performed after animals were subjected to RS using Plexiglas tubes. Results: The results demonstrated that RS produces analgesia in both phases of the formalin test. Intra-NAc injection of SCH-23390 equally reduced RS-induced analgesia in both early and late phases of the formalin test, while Sulpiride reduced RSinduced analgesia just at the late phase. Conclusions: These findings suggest that the dopaminergic system might act as a potential endogenous pain control system in stress conditions. However, the lack of evaluation of the role of the dopaminergic system in RS-induced antinociception in acute pain conditions is considered as a limitation for this study. In addition, a comprehensive evaluation of this endogenous pain control system in animal and clinical studies will guide future efforts for developing more effective medication. Significance: Restraint stress (RS) induces the antinociceptive behaviors in both phases of formalin test. Blockade of intra-accumbal dopamine receptors impresses the antinociception induced by RS. Blockade of D1-like dopamine receptor equally reduced RS-induced analgesia in both early and late phases of the formalin test.

The modulatory role of dopamine receptors within the hippocampal cornu ammonis area 1 in stress-induced analgesia in an animal model of persistent inflammatory pain

“…Moreover, based on the duration of stressors, various responses to pain have been observed in laboratory animals, such as SIA or stress-induced hyperalgesia (SIH). For example, one-time exposure to the RS (Faramarzi et al , 2021) or the FSS (Faramarzi et al , 2016) induces analgesia, whereas repeated swim stress (Quintero et al , 2000) and chronic daily exposure to the RS (Scheich et al , 2017) appeared to produce the SIH instead of the SIA.…”

“…Both rewarding and aversive stimuli, such as stressors, potently activate specific dopaminergic neurons in the VTA (Holly and Miczek, 2016). Previously, we have demonstrated that dopamine receptors within the NAc contribute to both forced swim stress (FSS) and restraint stress (RS)induced analgesia during persistent inflammatory pain (Faramarzi et al, 2016(Faramarzi et al, , 2021.…”

“…The results of functional MRI in healthy human subjects demonstrated that mental arithmetic combined with increasing noise levels as a stressor activates the insula and anterior cingulate cortex and results in higher poststress pain thresholds and increase in pain tolerance (Yilmaz et al , 2010). The animal studies also showed that major components of the limbic system, including the ventral tegmental area (VTA) (Askari et al , 2021), nucleus accumbens (NAc) (Faramarzi et al , 2021), amygdala (Veinante et al , 2013), as well as hippocampus (Ghasemzadeh and Rezayof, 2015) are involved in the SIA. PET scan in healthy human subjects demonstrated that psychological stress is associated with mesolimbic dopamine release in the ventral striatum of the brain (Pruessner et al , 2004).…”

D2-like dopamine receptors blockade within the dentate gyrus shows a greater effect on stress-induced analgesia in the tail-flick test compared to D1-like dopamine receptors

“…Nowadays, it is well-known that DA receptors are widely expressed in the different regions of the nervous system, playing their vital roles in neuromodulation (Klein et al ., 2019). In this regard, previously, it has been declared that D1R and D2R within the nucleus accumbens (NAc) (Faramarzi et al ., 2016, 2021) and hippocampal CA1 (Abdi Dezfouli et al ., 2022) modulate acute stress-induced analgesia (SIA) in persistent inflammatory pain. In continuation, a formalin test, as an algogenic substance-induced inflammatory pain, was performed, and it was indicated that DA receptors also within the hippocampal DG play the same modulatory role in SIA (Merdasi et al ., 2022).…”