The Role Of The Ventrolateral Orbital Cortex In Antinociception And Mood Modulation

The ventrolateral orbital cortex (VLO) in rat and cat is a major component of the orbital cortex, occupying a large region of the prefrontal cortex. Anatomical studies suggest that the VLO may be involved in regulation of various complex functions. Since the VLO receives a direct projection from thalamic nucleus submedius (Sm) and projects to periaqueductal gray (PAG), and the Sm has been demonstrated to be involved not only in nociception, but also in nociceptive modulation, it is reasonable to suspect that the VLO is involved as a higher center in nociceptive modulation of the Sm-VLO-PAG pathway. Furthermore, The complex connections between the orbitofrontal cortex and the amygdala, as well as other areas involved in emotion, suggest important implications for the role of the VLO in mood modulation. The present study examined : (1) The role of dopamine receptors in VLO-evoked anti-nociception in a rat model of neuropathic pain; (2) The roles of dopamine receptors in VLO-evoked antinociception in formalin test rats; (3) Effects of acute microinjection of histone deacetylases, sodium valproate (VPA), into the VLO in the rat forced swimming test. The results are as follows:1. Microinjection of apomorphine (1.0, 2.5, 5.0μg), a non-selective dopamine receptor agonist, into the VLO attenuated spared nerve injury (SNI)-induced mechanical allodynia in a dose-dependent manner. This effect was completely blocked by the D2- like dopamine receptor antagonist raclopride (1.5μg), but was enhanced by the D1-like dopamine receptor antagonist SCH23390 (5.0μg). The attenuating effect of apomorphine on mechanical allodynia was mimicked by application of the D2-like dopamine receptor agonist quinpirole (0.5, 1.0, and 2.0μg). In addition, microinjection of larger doses (10 and 20μg) of SCH23390 into the VLO significantly attenuated allodynia. Furthermore, microinjections of GABAA receptor antagonists, bicuculline and picrotoxin (200 and 300 ng for both drugs), into the VLO attenuated mechanical allodynia. A small dose of bicuculline or picrotoxin (100 ng) resulted in increased quinpirole (0.5μg)-induced anti-allodynia. In contrast, GABAA receptor agonists, muscimol hydrochloride (250 ng) or THIP (1.0μg), blocked quinpirole (2.0μg)-induced attenuation. These results suggest that the dopaminergic system is involved in mediating VLO-induced anti-hypersensitivity, activation of D2-like dopamine receptors, and inhibition of D1-like receptors resulting in anti-hypersensitivity. In addition, the mechanisms of GABAergic disinhibition might be involved in D2-like receptor mediating effects in neuropathic pain.2. Microinjection of a non-selective dopamine receptor agonist apomorphine (1.0, 2.5, 5.0μg) into the VLO depressed the later phase nociceptive behavior induced by formalin injected into the rat hindpaw, this effect was attenuated by D2-like dopamine receptor antagonist (3.0μg). The antinociception of apomorphine could be mimicked by microinjection of the D2-like dopamine receptor agonist quinpirole (1.0, 2.0 and 5.0μg) into the same VLO site. Furthermore, microinjection of the D1-like dopamine receptor antagonist SCH-23390 (2.5, 5.0, 10μg) into the VLO dose-dependently depressed the formalin-induced nociceptive behavior. These results suggest that the roles of D1-like and D2-like dopamine receptors in mediating the VLO-induced antinociception are different in the persistent inflammatory pain model, in which the D2-like receptors mediate the dopamine-induced antianociception, while the D1-like dopamine receptors have a tonic facilitatory action on the nociceptive behavior, thus block of the D1-like dopamine receptors produces antinociception.3. Acute microinjection of sodium valproate (VPA, 300μg) into the bilateral VLO decreased the immobility time of rats in the forced swimming test (FST), but did not influence the horizontal locomotion, which are similar to that typically seen in chronic intraperitoneal injection of standard antidepressant, fluoxetine (10mg/kg for 7 days). These results suggested that VPA may exert an antidepressant-like effect in rat FST through VLO-mediated functions in mood.