Rostral Agranular Insular Cortex Research Articles

Dopaminergic input to GABAergic neurons in the rostral agranular insular cortex of the rat.

Increasing evidence shows that the rostral agranular insular cortex (RAIC) is important in the modulation of nociception in humans and rats and that dopamine and GABA appear to be key neurotransmitters in the function of this cortical region. Here we use immunocytochemistry and path tracing to examine the relationship between dopamine and GABA related elements in the RAIC of the rat. We found that the RAIC has a high density of dopamine fibers that arise principally from the ipsilateral ventral tegmental area/substantia nigra (VTA/SN) and from a different set of neurons than those that project to the medial prefrontal cortex. Within the RAIC, there are close appositions between dopamine fibers and GABAergic interneurons. One target of cortical GABA appears to be a dense band of GABAB receptor-bearing neurons located in lamina 5 of the RAIC. The GABAB receptor-bearing neurons project principally to the amygdala and nucleus accumbens with few or no projections to the medial prefrontal cortex, cingulate gyrus, the mediodorsal thalamic nucleus or contralateral RAIC. The current anatomical data, together with previous behavioral results, suggest that part of the dopaminergic modulation of the RAIC occurs through GABAergic interneurons. GABA is able to exert specific effects through its action on GABAB receptor-bearing projection neurons that target a few subcortical limbic structures. Through these connections, dopamine innervation of the RAIC is likely to affect the motivational and affective dimensions of pain.

Dopamine Reuptake Inhibition in the Rostral Agranular Insular Cortex Produces Antinociception

We provide evidence for an antinociceptive effect of dopamine in the rat cerebral cortex that is mediated through descending nociceptive inhibition of spinal neurons. Injection of the dopamine reuptake inhibitor GBR-12935 in the rostral agranular insular cortex (RAIC), a cortical area that receives a dense dopaminergic projection and is involved in descending antinociception (Burkey et al.,1996), resulted in dose-dependent inhibition of formalin-induced nociceptive behavior, without any alteration of motor function. Injection of the dopamine reuptake inhibitor in the surrounding cortical areas had no effect on nociceptive behaviors. GBR-12935 also produced a reduction in noxious stimulus-induced c-fos expression in nociceptive areas of the spinal dorsal horn, suggesting that dopamine in the RAIC acts in part through descending antinociception. Electrophysiological recording from single wide dynamic range-type spinal dorsal horn neurons confirmed the descending nociceptive inhibitory effect. GBR-12935 in the RAIC significantly reduced neuronal responses evoked by noxious thermal stimulation of the skin, an effect that was reversed by local administration of the selective D1 receptor antagonist SCH-23390. Finally, administration of SCH-23390 alone in the RAIC decreased paw withdrawal latencies from noxious heat, suggesting that dopamine acts tonically in the cortex to inhibit nociception.

An Opioidergic Cortical Antinociception Triggering Site in the Agranular Insular Cortex of the Rat that Contributes to Morphine Antinociception

We report an anatomically defined opioid-responsive site in the rostral agranular insular cortex (RAIC) of the rat and characterize the antinociception produced by morphine acting within this region. Immunohistochemistry for the mu-opioid receptor identified a discretely localized cluster of densely labeled dendrite-like processes in the agranular insular cortex. The antinociceptive effect of morphine microinjected unilaterally into this area was evaluated using the formalin test. Antinociception was observed in both ipsilateral and contralateral hindpaws. Local pretreatment with naltrexone in the RAIC blocked the antinociception of local morphine injection, confirming that morphine was acting at an opioid receptor. Unilateral injection of naloxone methiodide into the RAIC reversed the behavioral antinociception of systemic morphine bilaterally in the formalin test. Evidence for a descending inhibitory mechanism acting on spinal nociceptive neurons was obtained by monitoring noxious stimulus-induced c-fos expression in rats having undergone formalin testing and by electrophysiological recording of single units in the lumbar dorsal horn after localized application of morphine into the RAIC. A significant reduction in the number of Fos-like immunoreactive neurons was found ipsilateral to the formalin stimulus in nociresponsive areas of the dorsal horn after on-site injections of morphine into the RAIC. Electrophysiological recording of nociresponsive dorsal horn neurons demonstrated a naloxone-reversible reduction in noxious thermal stimulus-evoked firing after morphine injection into this same area. These results suggest that the RAIC contributes to opioid-receptor-mediated antinociception after either local or systemic morphine administration and that these effects may be associated with an increased descending inhibition of dorsal horn neurons.