<p>Role of Dopaminergic Receptors Within the Ventral Tegmental Area in Antinociception Induced by Chemical Stimulation of the Lateral Hypothalamus in an Animal Model of Orofacial Pain</p>

Abstract

Introduction:The ventral tegmental area (VTA), as one of the classical components of the brain reward circuitry, shares large neural networks with the pain processing system. We previously showed the role of VTA dopamine receptors in modulation of lateral hypothalamus (LH)-induced antinociception in acute pain conditions. However, considering the fact that the neural systems involved in the mediation of tonic pain are not the same as those that mediate phasic pain. In the present study, we aimed to examine the role of intra-VTA dopamine receptors in LH-induced antinociceptive responses during tonic orofacial pain conditions. Methods: Male Wistar rats weighing 230-250 g were implanted with two separate cannulae into the LH and VTA on the same side. Different solutions of carbachol (62.5, 125 and 250 nM), as a non-selective cholinergic receptor agonist that activates the LH projecting neurons, were microinjected into the LH. In the other groups, D1-like dopamine receptor antagonist, SCH-23390 (0.25, 1 and 4 µg/03 µL saline) or D2-like dopamine receptor antagonist, Sulpiride (0.25, 1 and 4 µg/0.3 µL DMSO 12%) were microinjected into VTA, 5 min prior intra-LH carbachol (250 nM), then subjected to orofacial formalin test. Intra-LH carbachol microinjection dose-dependently attenuated biphasic orofacial pain. Results: Intra-VTA administration of SCH-23390 or Sulpiride dose-dependently decreased intra-LH carbachol-induced antinociception during both phases of orofacial formalin test with further effects in the late phase. Discussion: The findings suggest that chemical stimulation of the LH by carbachol possibly activates the orexin projecting neurons and subsequently, the VTA dopaminergic neurons involved in the orofacial pain modulation. Detecting such neural circuitry offers an alternative approach in the development of more efficient therapies for such debilitating pain conditions.

Involvement of Dopaminergic System in the Dentate Gyrus of the Hippocampus in Modulating the Orofacial Pain-Related Behaviors in the Rats

“…The present study results demonstrated that blockade of dopamine receptors within the DG region could completely block the antinociceptive responses induced by chemical stimulation of LH following formalin injection into the orofacial region. In this regard, the previous study revealed that the dopaminergic receptors located in the VTA contributes in antinociception induced by chemical stimulation of LH during orofacial pain in rats (Matini et al, 2020). In addition, the role of dopaminergic receptors in the NAc in antinociceptive response-induced by chemical stimulation of LH has been demonstrated in formalin-induced orofacial pain (Shafiei et al, 2018).…”

“…Besides, a positron emission tomography (PET) study on patients with burning mouth syndrome showed a decrease in the D1/ D2 ratio and dopamine hypofunction in the nigrostriatal dopaminergic pathway (Hagelberg et al, 2003). It has been shown that dopaminergic receptors within the VTA (Matini et al, 2020) and NAc (Haghparast et al, 2020) modulate the antinociceptive responses induced by chemical stimulation of the LH in an animal model of orofacial pain.…”

Neuroanatomical Basis for the Orexinergic Modulation of Anesthesia Arousal and Pain Control

“…In addition to the arousal effect, we found that activating orexin neurons in the lateral hypothalamus can increase the animal’s tolerance to painful stimuli. Many of the orexin projected brain regions are also involved in the pain control, such as BST, central amygdala nucleus, dorsal nucleus raphe, laterodorsal tegmental area, lateral habenula, PAG, parabrachial nucleus, PVT, and VTA, which may underlie the analgesic effects by orexin neurons ( Kooshki et al, 2020 ; Matini et al, 2020 ). Further work is needed to study the involvement of different nuclei in pain control.…”

Involvement of dopaminergic system in the dentate gyrus of the hippocampus in modulating the orofacial pain-related behaviors in the rats

“…LH stimulation could also reduce hyperalgesia through orexin-A neurons in an animal model of neuropathic pain (Wardach et al , 2016). Moreover, the effect of LH stimulation on dopaminergic receptors within the VTA in attenuating orofacial pain has also been demonstrated (Matini et al , 2020). Orexin neurons project from the LH to dopaminergic neurons in the VTA, and VTA dopamine neurons project to the nucleus accumbens (NAc), amygdala, hippocampus, and prefrontal cortex, forming the mesocorticolimbic dopamine system (Korotkova et al , 2003).…”