Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex

Abstract

It is known that pain perception can be altered by mood, attention and cognition, or by direct stimulation of the cerebral cortex, but we know little of the neural mechanisms underlying the cortical modulation of pain. One of the few cortical areas consistently activated by painful stimuli is the rostral agranular insular cortex (RAIC) where, as in other parts of the cortex, the neurotransmitter gamma-aminobutyric acid (GABA) robustly inhibits neuronal activity. Here we show that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold--producing analgesia or hyperalgesia, respectively--in freely moving rats. Locally increasing GABA, by using an enzyme inhibitor or gene transfer mediated by a viral vector, produces lasting analgesia by enhancing the descending inhibition of spinal nociceptive neurons. Selectively activating GABA(B)-receptor-bearing RAIC neurons produces hyperalgesia through projections to the amygdala, an area involved in pain and fear. Whereas most studies focus on the role of the cerebral cortex as the end point of nociceptive processing, we suggest that cerebral cortex activity can change the set-point of pain threshold in a top-down manner.

Pharmacological and Behavioral Characteristics of Interactions between Vigabatrin and Conventional Antiepileptic Drugs in Pentylenetetrazole-Induced Seizures in Mice: An Isobolographic Analysis

“…This VGBmediated antinociceptive effect was reversed by coinjection with the GABA A receptor antagonist bicuculline, providing evidence that the observed analgesic effect is dependent on the increased GABA concentration (Jasmin et al, 2003). Moreover, it has been observed that systemic (i.p.)…”

“…Quite recently, in in vivo experiments, it has been found that the direct microinjection of VGB into the rostral agranular insular cortex (RAIC) in rats resulted in a clear and consistent analgesia (Jasmin et al, 2003). This VGBmediated antinociceptive effect was reversed by coinjection with the GABA A receptor antagonist bicuculline, providing evidence that the observed analgesic effect is dependent on the increased GABA concentration (Jasmin et al, 2003).…”

Cortical processing of tactile stimuli applied in quick succession across the fingertips: temporal evolution of dipole sources revealed by magnetoencephalography

“…Insula is known to be an integration region for temperature, hunger, thirst, air hunger, and pain (Craig 2002;Frot et al 2007). The insular cortex participates in acute and inXammatory nociception, and it has been involved in the descending pain modulation system (Burkey et al 1996(Burkey et al , 1999Jasmin et al 2003). With respect to the trigeminal nerve, Alvarez et al (2009) demonstrated that the process of tactile stimulus can be changed in the insular cortex after trigeminal nerve injury in rats (Alvarez et al 2009).…”

Immune and inflammatory gene signature in rat cerebrum in subarachnoid hemorrhage with microarray analysis

“…The metabotropic GABA B receptors are coupled to G proteins and modulate synaptic transmission through intracellular effector systems of the mammalian central nervous system (25). GABA B receptors function by inhibiting presynaptic transmitter release or by increasing the potassium conductance responsible for long-lasting inhibitory postsynaptic potentials (26,27). However, the mechanisms leading to decreased KZF-2 and GABA B receptor expression in SAH have not yet been characterized.…”