Modulatory role of intra-accumbal dopamine receptors in the restraint stress-induced antinociceptive responses.

Stress contributes to pain sensation by affecting several neural pathways, including mesolimbic-cortical dopamine neurons. Nucleus accumbens, an essential element of the mesolimbic dopaminergic pathway, plays a fundamental role in modulating pain and is differentially influenced by stressful events. Since we previously demonstrated the marked association of intra-NAc dopamine receptors with forced swim stress-evoked analgesia in acute pain state, this research was conducted to consider the contribution of intra-accumbal D1- and D2-like dopamine receptors to modulating effects of exposure to restraint stress in pain-related behaviors during the tail-flick test. Stereotaxic surgery was executed to implant a guide cannula within the NAc in male Wistar rats. On the test day, different concentrations of SCH23390 and Sulpiride as D1- and D2-like dopamine receptor antagonists, respectively, were unilaterally microinjected within the NAc. The vehicle animals received saline or 12 % DMSO (0.5 µl) instead of SCH23390 or Sulpiride into the NAc, respectively. Five minutes following receiving drug or vehicle, animals were restrained for 3 h and then their acute nociceptive threshold was measured for a 60-min period by the tail-flick test. Our data revealed that RS considerably enhanced antinociceptive reaction in acute pain states. The analgesia evoked by RS dramatically declined following blocking either D1- or D2-like dopamine receptors in the NAc, an effect was more noticeable by D1-like dopamine receptor antagonist. These findings indicated that intra-NAc dopamine receptors are considerably mediated in the RS-produced analgesia in acute pain states, suggesting their possible role in psychological stress and disease.

Nucleus accumbens dopamine receptors mediate the stress-induced analgesia in an animal model of acute pain.

Exposure to aversive stimuli such as stress results in profound analgesia named stress-induced analgesia (SIA). We previously showed that D1- and D2-like dopamine receptors within the nucleus accumbens (NAc) mediated the SIA in chronic pain. Since the neurophysiological mechanisms responsible for the various pain conditions are different, the present study aimed to examine the role of dopamine receptors within the NAc in the forced swim stress (FSS)-induced analgesia in the tail-flick test as an animal model of acute pain. Ninety-six adult male Wistar rats weighing 200-230 g were unilaterally implanted with a cannula into the NAc. SCH23390 or Sulpiride (0.25, 1, and 4 µg/0.5 µl vehicle), as D1- and D2-like dopamine receptor antagonists, respectively, were microinjected into the NAc, 5 min before exposure to FSS. The vehicle groups received saline or DMSO instead of SCH23390 or Sulpiride, respectively. The tail-flick test was performed in time set intervals after animals were subjected to FSS. The results showed that FSS produces analgesia during the tail-flick test. However, intra-accumbal injection of SCH23390 or Sulpiride attenuated the FSS-induced analgesia. D1-and D2-like dopamine receptor antagonists contributed almost equally to attenuating the antinociceptive responses induced by FSS. It seems that the mesolimbic dopamine system might act as a potential endogenous pain control system in stress conditions. Besides, an improved understanding of this endogenous pain inhibitory system can develop pharmacological and psychological approaches to treat pain.

Intranasal insulin improves the structure-function of the brain mitochondrial ATP-sensitive Ca2+ activated potassium channel and respiratory chain activities under diabetic conditions.

Although it is well established that diabetes impairs mitochondrial respiratory chain activity, little is known of the effects of intranasal insulin (INI) on the mitochondrial respiratory chain and structure-function of mitoBKCa channel in diabetes. We have investigated this mechanism in an STZ-induced early type 2 diabetic model. Single ATP-sensitive mitoBKCa channel activity was considered in diabetic and INI-treated rats using a channel incorporated into the bilayer lipid membrane. Because mitoBKCa channels have been involved in mitochondrial respiratory chain activity, a study was undertaken to investigate whether the NADH, complexes I and IV, mitochondrial ROS production, and ΔΨm are altered in an early diabetic model. In this work, we provide evidence for a significant decrease in channel open probability and conductance in diabetic rats. Evidence has been shown that BKCa channel ß2 subunits induce a left shift in the BKCa channel voltage dependent curve in low Ca2+ conditions,; our results indicated a significant decrease in mitoBKCa ß2 subunits using Western blot analysis. Importantly, INI treatment improved mitoBKCa channel behaviors and ß2 subunits expression up to ~70%. We found that early diabetes decreased activities of complex I and IV and increased NADH, ROS production, and ΔΨm. Surprisingly, INI modified the mitochondrial respiratory chain, ROS production, and ΔΨm up to ~70%. Our results thus demonstrate an INI improvement in respiratory chain activity and ROS production in brain mitochondrial preparations coming from the STZ early diabetic rat model, an effect potentially linked to INI improvement in mitoBKCa channel activity and channel ß2 subunit expression.