Modulation of μ-opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase γ

König, Christian; Gavrilova-Ruch, O.; Banchet, Gisela Segond von; Bauer, Reinhard; Grün, M.; Hirsch, Emilio; Rubio, Ignacio; Schulz, Stefan; Heinemann, Stefan H.; Schaible, Hans Georg; Wetzker, Reinhard

doi:10.1016/j.neuroscience.2010.04.068

Cited by 28 publications

(26 citation statements)

References 24 publications

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“…Originally, this signalling protein was characterized as a master mediator of leukocyte functions in inflammation (Hirsch et al, 2000). Recent studies extended this view and revealed that PI3Kγ is an essential element of pain-relieving opioid effects in neuronal cells (Cunha et al, 2010;König et al, 2010). Our investigations in the cell line μ-SK-N-LO confirmed these results.…”

Section: Discussionsupporting

confidence: 80%

PI3Kγ integrates cAMP and Akt signalling of the μ‐opioid receptor

Madishetti

Schneble

König

et al. 2014

British J Pharmacology

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Background and PurposeThe μ‐opioid receptor has been characterized as the main mediator of opioid signalling in neuronal cells. Opioid‐induced pain suppression was originally proposed to be mediated by μ‐opioid receptor‐induced inhibitory effects on cAMP, which is known to mediate inflammatory hypernociception. Recent investigations revealed PI3Kγ and Akt (PKB) as additional elements of μ‐opioid receptor signalling. Hence, we investigated the interaction between pronociceptive cAMP and antinociceptive PI3K/Akt signalling pathways.Experimental ApproachThe human neuroblastoma cell line SK‐N‐LO and primary dorsal root ganglia (DRG) cells from mice were used to elucidate mediators of μ‐opioid receptor signalling. In both cellular systems cAMP was manipulated by stimulation of adenylate cyclase and consequent effects on PI3K/Akt signalling were analysed.Key ResultsMorphine stimulated Akt phosphorylation on Ser473 and Thr308 in a dose‐ and time‐dependent manner indicating a functional μ‐opioid receptor/Akt signalling pathway in μ‐SK‐N‐LO cells. This effect of morphine was suppressed by the μ‐opioid receptor inhibitor, naloxone, Pertussis toxin, an inhibitor of Gi heterotrimeric G‐proteins, and the pan PI3K inhibitor wortmannin. cAMP‐elevating agents also suppressed μ‐opioid receptor‐dependent stimulation of PI3Kγ lipid kinase and Akt activities in SK‐N‐LO cells and DRG.Conclusions and ImplicationsThe data unveil a hitherto unknown interaction of pronociceptive cAMP and antinociceptive PI3K/Akt signalling pathways in neuronal cells. PI3Kγ was identified as a mediator of the inhibitory action of cAMP on Akt in SK‐N‐LO cells and DRG. The data indicate that PI3Kγ has a critical role in cAMP‐mediated inflammatory hypernociception and analgesic signalling via μ‐opioid receptors and PI3K/Akt in neuronal cells.

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Section: Discussionsupporting

confidence: 80%

PI3Kγ integrates cAMP and Akt signalling of the μ‐opioid receptor

Madishetti

Schneble

König

et al. 2014

British J Pharmacology

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“…In DRG tissue, however, we detected mRNA for PI3Kγ and staining for the protein was seen in the soma of a subpopulation of small to medium sized, presumptive nociceptive DRG neurons (Figure 4C,D). Staining in IB4 and TRPV1 expressing DRG neurons and lack of staining in the spinal cord has previously been reported for this isoform [13; 25]. Four h post paw carrageenan, levels of PI3Kγ mRNA were seen to decrease in dorsal spinal cord (p≤ 0.047) and to remain stable in DRG (p≤ 0.423).…”

Section: Resultsmentioning

confidence: 55%

“…These investigators also reported that mRNA for all four PI3K isoforms is present in the DRG and trigeminal ganglia. More recently, PI3Kγ has been identified in small to medium size neurons, which double stained for IB4 or TRPV1 [13; 25]. Interestingly, PI3Kδ has been reported in the ventral horn and peripheral nervous system of E13.5 mice and PI3Kδ knock out mice display reduced nerve regeneration post injury [18], this raises the possibility that different isoforms are expressed during development and under conditions of regeneration or extreme physiological stress.…”

Section: Discussionmentioning

confidence: 99%

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

Leinders

Koehrn

Bartók

et al. 2014

Pain

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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.

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“…PI3Kγ, the only G-protein coupled PI3K, is expressed in TRPV1-positive peripheral sensory neurons in both rats and mice [32], [33] and has been implicated in morphine-induced peripheral analgesia [32] and morphine tolerance [33]. Use of non-specific inhibitors, like wortmannin, has suggested a role for PI3' kinases in producing NGF-mediated TRPV1 sensitization [21],[34].…”

Section: Resultsmentioning

confidence: 99%

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

Neely

Costigan

et al. 2012

PLoS Genet

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The ability to perceive noxious stimuli is critical for an animal's survival in the face of environmental danger, and thus pain perception is likely to be under stringent evolutionary pressure. Using a neuronal-specific RNAi knock-down strategy in adult Drosophila, we recently completed a genome-wide functional annotation of heat nociception that allowed us to identify α2δ3 as a novel pain gene. Here we report construction of an evolutionary-conserved, system-level, global molecular pain network map. Our systems map is markedly enriched for multiple genes associated with human pain and predicts a plethora of novel candidate pain pathways. One central node of this pain network is phospholipid signaling, which has been implicated before in pain processing. To further investigate the role of phospholipid signaling in mammalian heat pain perception, we analysed the phenotype of PIP5Kα and PI3Kγ mutant mice. Intriguingly, both of these mice exhibit pronounced hypersensitivity to noxious heat and capsaicin-induced pain, which directly mapped through PI3Kγ kinase-dead knock-in mice to PI3Kγ lipid kinase activity. Using single primary sensory neuron recording, PI3Kγ function was mechanistically linked to a negative regulation of TRPV1 channel transduction. Our data provide a systems map for heat nociception and reinforces the extraordinary conservation of molecular mechanisms of nociception across different species.

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Modulation of μ-opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase γ

Cited by 28 publications

References 24 publications

PI3Kγ integrates cAMP and Akt signalling of the μ‐opioid receptor

PI3Kγ integrates cAMP and Akt signalling of the μ‐opioid receptor

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

Construction of a Global Pain Systems Network Highlights Phospholipid Signaling as a Regulator of Heat Nociception

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