Differential distribution of PI3K isoforms in spinal cord and dorsal root ganglia: Potential roles in acute inflammatory pain

Abstract

PI3-kinases (PI3Ks) participate in nociception within spinal cord, dorsal root ganglion (DRG) and peripheral nerves. To extend our knowledge, we immunohistochemically stained for each of the four Class I PI3K isoforms along with several cell specific markers within lumbar spinal cord, DRG and sciatic nerve of naïve rats. Intrathecal and intraplantar isoform specific antagonists were given as pre-treatments before intraplantar carrageenan; pain behavior was then assessed over time. The α-isoform was localized to central terminals of primary afferent fibers in spinal cord laminae IIi-IV as well as to neurons in ventral horn and DRG. The PI3Kβ isoform was the only Class I isoform seen in dorsal horn neurons, it was also observed in DRG, Schwann cells and axonal paranodes. The δ-isoform was found in spinal cord white matter oligodendrocytes and radial astrocytes, while the γ-isoform was seen in a subpopulation of IB4-positive DRG neurons. No isoform co-localized with microglial markers or satellite cells in naïve tissue. Only the PI3Kβ antagonist, but none of the other antagonists, had anti-allodynic effects when administered intrathecally; coincident with reduced pain behavior, this agent completely blocked paw carrageenan-induced dorsal horn 2-amino-3-(3-hydroxy-5-methylisoxazol- 4-yl) propanoic acid (AMPA) receptor trafficking to plasma membranes. Intraplantar administration of the γ-antagonist prominently reduced pain behavior. These data suggest that each isoform displays specificity with regard to neuronal type as well as to specific tissues. Furthermore, each PI3K isoform has a unique role in development of nociception and tissue inflammation.

Phosphoinositide 3-kinase β, phosphoinositide 3-kinase δ, and phosphoinositide 3-kinase γ mediate the anti-inflammatory effects of magnesium sulfate

“…In addition, PI3Kb has been shown to modulate inflammatory mediator thromboxane A 2 expression in platelets [29]. Recent data also indicated that PI3Kb plays a crucial role in modulating acute inflammation pain [30]. Collectively, these data demonstrate the involvement of PI3Ka and/or PI3Kb in a broad range of pathophysiologies, which are consistent with the possible involvement of PI3Ka and/or PI3Kb in mediating the anti-inflammatory effects of MgSO 4 .…”

Lipid kinases as therapeutic targets for chronic pain

“…Therefore, it is important to study the expression patterns of these isoforms and fully dissect the signaling pathways that each is involved in. PI3Kα, β and γ but not δ are expressed in DRGs [45; 5]. PI3Kα is ubiquitously expressed in sensory neurons.…”

“…PI3Kα is ubiquitously expressed in sensory neurons. PI3Kβ is expressed in spinal cord dorsal horn neurons and enhances AMPA receptor trafficking upon inflammation, resulting in increase excitatory synaptic transmission [45]. PI3Kδ is reportedly not expressed in the DRG but is found in astrocytes in the spinal cord dorsal horn [45].…”

“…PI3Kβ is expressed in spinal cord dorsal horn neurons and enhances AMPA receptor trafficking upon inflammation, resulting in increase excitatory synaptic transmission [45]. PI3Kδ is reportedly not expressed in the DRG but is found in astrocytes in the spinal cord dorsal horn [45]. Even though this isozyme does not seem to regulate nociceptive sensitization, it has important roles during development and in nerve regeneration after injury [21].…”

“…Surprisingly, PI3Kγ knockout ( Pik3cg −/− ) mice exhibit enhanced responses to heat and capsaicin, suggesting that PI3Kγ acts as a negative regulator of thermal and TRPV1 responses [60]. Interestingly, antagonism of this isozyme with a specific inhibitor in the periphery (via intraplantar injections) was shown to be anti-allodynic in a carrageenan-induced allodynia model [45]. The earlier finding of PI3Kγ negatively regulating TRPV1 activity only focused on acute thermal nociception and TRPV1 channel activity but did not look at the role of PI3Kγ in NGF-induced TRPV1 sensitization or in neuropathic and inflammatory pain models.…”