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.

INTRODUCTION: Acute stress, as a protective mechanism to respond to an aversive stimulus, can often be accompanied by suppressing pain perception via promoting consistent burst firing of dopamine neurons. Besides, sensitive and advanced research techniques led to the recognition of the mesohippocampal dopaminergic terminals, particularly in the hippocampal dentate gyrus (DG). Moreover, previous studies have shown that dopamine receptors within the hippocampal DG play a critical role in induced antinociceptive responses by forced swim stress (FSS) in the presence of inflammatory pain. Since different pain states can trigger various mechanisms and transmitter systems, the present experiments aimed to investigate whether dopaminergic receptors within the DG have the same role in the presence of acute thermal pain. METHODS: Ninety-seven adult male albino Wistar rats underwent stereotaxic surgery, and a stainless steel guide cannula was unilaterally implanted 1 mm above the DG. Different doses of SCH23390 or sulpiride as D1- and D2-like dopamine receptor antagonists were microinjected into the DG 5-10 min before exposure to FSS, and 5 min after FSS exposure, the tail-flick test evaluated the effect of stress on the nociceptive response at the time-set intervals. RESULTS: The results demonstrated that exposure to FSS could significantly increase the acute pain perception threshold, while intra-DG administration of SCH23390 and sulpiride reduced the antinociceptive effect of FSS in the tail-flick test. DISCUSSION: Additionally, it seems the D2-like dopamine receptor within the DG plays a more prominent role in FSS-induced analgesia in the acute pain model.

Blocking the dopaminergic receptors within the hippocampal dentate gyrus reduced analgesic responses induced by restraint stress in the formalin test.

Previous studies have shown that various receptors, including dopamine receptors, are expressed in the hippocampal dentate gyrus (DG). Besides, indicatively, dopamine receptors play an essential role in the modulation of pain perception. On the other hand, stressful experiences can produce analgesia, termed stress-induced analgesia (SIA). The current study examined the probable role of dopamine receptors within the DG in antinociception induced by restraint stress (RS). Ninety-seven male albino Wistar rats were unilaterally implanted with a cannula in the DG. Animals received intra-DG microinjections of SCH23390 or Sulpiride (0.25, 1, and 4 µg/rat) as D1-and D2-like dopamine receptor antagonists, respectively, five minutes before RS. Ten minutes after the end of the induction of RS for three hours, 50 µl 2.5% formalin was injected subcutaneously into the plantar surface of the hind paw to induce persistent inflammatory pain. Pain scores were evaluated at 5-minute intervals for 60 minutes. These findings showed that; exposure to RS for three hours produced SIA in both phases of the formalin test, while this RS-induced analgesia was attenuated in the early and late phases of the formalin test by intra-DG microinjection of SCH23390 and Sulpiride. The results of the present study suggested that both D1- and D2-like dopamine receptors in the DG have a considerable role in the induced analgesia by RS.

The integrative role of orexin-1 and orexin-2 receptors within the hippocampal dentate gyrus in the modulation of the stress-induced antinociception in the formalin pain test in the rat.

The stressful experiences, by triggering a cascade of hormonal and neural changes, can produce antinociception commonly referred to as stress-induced antinociception (SIA). Orexin neuropeptides have an essential role in stress responses and pain modulation. The dentate gyrus receives orexinergic projections and has been shown to be involved in pain processing. The current study investigated the possible role of orexin-1 and orexin-2 receptors (OX1r and OX2r, respectively) within the dentate gyrus in SIA in a rat model of formalin-induced pain behavior in one hind paw. Male Wistar rats weighing 230-250 g underwent stereotaxic surgery and a cannula was implanted in their brains, above the dentate gyrus region. Either SB334867 or TCS OX2 29 (OX1r and OX2r antagonists, respectively) was microinjected into the dentate gyrus region at a range of doses at 1, 3, 10, and 30 nmol (control group received DMSO 12% as vehicle), 5 min before the forced swim stress (FSS) exposure. The formalin test was performed to assess pain-related behaviors. The results indicated that FSS exposure relieves pain-related behavior in the early and late phases of the formalin test. Blockade of intra-dentate gyrus OX1 or OX2 receptors reduced the antinociceptive responses induced by FSS in the formalin test, with more impact during the late phase. Our findings support the potential role of intra-dentate gyrus orexin receptors as target sites of orexin neurons in painful and stressful situations. Therefore, understanding the exact mechanisms of SIA and the role of the orexinergic system in this phenomenon can lead to identifying the strategies to guide future research and offer a new approach to discovering new pain therapeutic agents.

Restraint stress potentiates sensitivity to the antinociceptive effect of morphine through orexin receptors in the ventral tegmental area.

Orexin signaling in the ventral tegmental area (VTA) plays a critical role in stress and addictive behaviors. On the other hand, exposure to stress potentiates behavioral sensitization to drugs of abuse such as morphine. This study aimed to elucidate the role of orexin receptors within the VTA in restraint stress (RS)-induced morphine sensitization. Adult male albino Wistar rats underwent stereotaxic surgery, and two stainless steel guide cannulae were bilaterally implanted into the VTA. Different doses of SB334867 or TCS OX2 29 as orexin-1 (OX1) and orexin-2 (OX2) receptor antagonists were microinjected into the VTA five min before exposure to RS, respectively. A duration of three hours was considered for applying the RS, and 10 min after RS exposure, animals received a subcutaneous injection of an ineffective dose of morphine (1 mg/kg) for three consecutive days followed by a five-day drug/stress-free period. On the ninth day, the tail-flick test evaluated the sensitivity to the antinociceptive effects of morphine. The results demonstrated that the sole application of RS or morphine (1 mg/kg) could not induce morphine sensitization; however, concurrent application of RS and morphine could induce morphine sensitization. Besides, intra-VTA administration of OX1 R or OX2 R antagonists before paired administration of morphine and RS blocked morphine sensitization. The role of OX1 R and OX2 R in the induction of stress-induced morphine sensitization was almost identical. This study provides new insight into the role of orexin signaling in the VTA in the potentiation of morphine sensitization induced by RS and morphine co-administration.

Restraint stress induced the antinociceptive responses via the dopamine receptors within the hippocampal CA1 area in animal model of persistent inflammatory pain.

It has been declared that dopamine receptors within the hippocampal formation are involved in emotion, memory, and pain processing. Remarkably, both CA1 and dentate gyrus (DG) areas of the hippocampal formation are involved in persistent peripheral nociceptive perception. A prior study showed that dopamine receptors within the hippocampal DG have a critical role in antinociception induced by forced swim stress (FSS), as a physical stressor, in the presence of formalin irritation. The present experiments were designed to assess whether dopaminergic receptors within the CA1 have any role in antinociceptive responses induced by restraint stress (RS) as a psychological stressor after applying the formalin test as an animal model of persistent inflammatory pain. The D1- and D2-like dopamine receptor antagonists, SCH23390 and Sulpiride (0.25, 1, and 4 µg/0.5 µl), were injected into the CA1 areas of ninety-six male albino Wistar rats 5 min before a 3-h period of restraint stress. Ten min after stress termination, a 50-µl formalin 2.5 % was subcutaneously injected into the plantar surface of the rat's hind paw to induce persistent inflammatory pain. Nociceptive behaviors in both phases of the formalin test were analyzed in the 5-min blocks for a 60-min period. The obtained results demonstrate that although RS could induce an antinociceptive response in both phases of the formalin test, microinjection of D1- and D2-like dopamine receptors, antagonists attenuated RS-induced analgesia. These results support the hypothesis that acute restraint stress could induce analgesia via dopaminergic projection to the CA1 region of the hippocampal formation.

Blocking the dopaminergic receptors in the hippocampal dentate gyrus reduced the stress-induced analgesia in persistent inflammatory pain in the rat.

Although the dentate gyrus (DG) as a component of the hippocampal formation has been well known for its role in memory, various studies showed a diverse population of unique cell types and various inputs and outputs in this region. Besides, brain dopamine is known for its roles in reward, motivation, pleasure, and being involved in the pain process. Further, previous studies demonstrated the participation of DG dopaminergic receptors in antinociception induced by lateral hypothalamus stimulation. This study aimed to investigate the role of DG dopaminergic receptors (D1- and D2-like dopamine receptors) in stress-induced analgesia (SIA) using the formalin test as a persistent inflammatory pain model. One hundred two male Wistar rats were unilaterally implanted with a cannula into the DG. Animals received an intra-DG infusion of SCH23390 (0.25, 1, and 4 µg/rat), or Sulpiride (0.25, 1, and 4 µg/rat) as D1- and D2-like dopamine receptor antagonists, respectively, five min before exposure to forced swim stress (FSS). Ten minutes after FSS termination, 2.5% formalin solution as an inflammatory agent was subcutaneously injected into the plantar surface of the hind paw, and the pain score was quantified for one hour. The findings revealed that exposure to FSS produced SIA, though this FSS-induced analgesia was attenuated in the early and late phase of the formalin test by intra-DG microinjection of SCH23390 or Sulpiride. These results suggested that both D1- and D2-like dopamine receptors in the DG have a considerable role in analgesia induced by FSS.

Role of orexinergic receptors within the ventral tegmental area in the development of morphine sensitization induced by forced swim stress in the rat.

The ventral tegmental area (VTA) has been suggested as part of a common system for reward, stress, and morphine sensitization. Repeated exposure to stress enhances sensitivity to drugs such as morphine. The role of orexin receptor type 1 (OX1R) and type 2 (OX2R) within the VTA in cross-sensitization of morphine with stress was assessed in this study. Various doses of OX1R antagonist (SB334867) and OX2R antagonist (TCS OX2 29) were microinjected into the VTA of 134 adult male albino Wistar rats through cannulae, which had been bilaterally implanted above this region. Five min after microinjection, animals were forced to swim for 6 min, and 10 min after forced swim stress (FSS) termination, a low dose of morphine (i.e., ineffective dose for sensitization) was subcutaneously injected (1 mg/kg; sc). This procedure was repeated for three consecutive days as a sensitization period followed by a 5-day drug/stress-free period. On the 9th day, sensitivity to morphine was examined by measuring antinociceptive responses to the ineffective dose of morphine via tail-flick test. The obtained findings revealed that while concurrent administration of FSS and an ineffective dose of morphine (1 mg/kg; sc) for three consecutive days induced sensitivity to morphine, intra-VTA administration of OX1R- and OX2R antagonists, dose-dependently blocked this sensitization. These results suggested that both orexin receptors located in the VTA have a considerable role in morphine sensitization induced by concurrent administration of FSS and a low dose of morphine. So, there is a contribution of the orexin system partly to stress-induced sensitization to morphine.