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

Abstract

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.

Epileptiform synchronization in the rat insular and perirhinal cortices in vitro

“…Specifie localization of ~-opioid receptors combined with a direct assessment of effects on GABAergic neurotransmission at the synaptic level within the PC and the le will more specifically resolve the mode of opioid receptor action within these structures, however. Interestingly, direct application of opioids or locally increasing GA BA concentrations within the RAIC both result in long-lasting analgesia in rats (Burkey et al, 1996;Jasmin et al, 2003); however the manner by which these signaling pathways interact remains unknown. We have provided preliminary evidence that a similar mechanism to that in hippocampus occurs within the RAIC, although precisely how j.…”

“…Though the exact mechanism is unknown, IC outputs chronically regulate detection thresholds for painful stimuli in the periphery via GABAergic signais (Jasmin et al, 2003;Jasmin et aL, 2004). In addition, an unusually dense staining region for ~-opioid receptors (primary receptor targets for analgesia-producing opiates such as morphine) is present in the rostral agranular region (Delfs et aL, 1994;Burkey et aL, 1996). Of interest here, the IC is connected with other structures involved in TLE, such as the anterior hippocampus, the PC and the amygdala.…”

“…4AP application results in downregulation of the KCC2 co-transporter in hippocampal slices, resulting in intracellular CI-accumulation and hence depolarizing postsynaptic responses to GABA (Rivera et aL, 2004). It is thus possible that these potentials were not completely abolished despite the presence of DAGO due to strong somatic excitation mediated by interneuron recurrent collateral release of depolarizing GABA, to lead to large synchronized interneuronal network discharges (Michelson and Wong, 1994 (Delfs et aL, 1994;Burkey et aL, 1996;Jasmin et aL, 2003). The increased abundance of IJ-opioid receptors within the IC therefore may account for differences in response to DAGO between the PC and the IC, however more experimentation would be necessary to determine precisely how these phenomena relate.…”

“…The rostral agranular IC, in particular, is important in regulating peripheral nociceptive thresholds via opioidergic, dopaminergic and GABAergic signaling (Burkey et aL, 1996;Burkey et aL, 1999;Jasmin et al, 2003;Jasmin et aL, 2004). In addition, the rostral agranular IC is reciprocally connected with the perirhinal cortex (PC) (Delatour and Witter, 2002), a structure central in object memory and recognition (Buckley, 2005;Murray et al, 2005).…”

The Insular Cortex and the Amygdala: Shared Functions and Interactions

“…Each subdivision is believed to process particular sensory information. For example, the AI is believed to participate in nociceptive [4][5][6] and autonomic processing [3], the DI plays a role in gustatory processing [7,8] and the GI has an important role in modulating visceral function [3].…”