Background & Aims

Pain biomarkers could both elaborate pain mechanism and indicate therapeutic target engagement. Evoked brain activation could serve as a quantitative pain biomarker. Lysophosphatidic acid (LPA) is a neuroinflammatory lipid that has been shown to contribute to the development and maintenance of neuropathic pain. Furthermore, blocking LPA signaling through the LPA1 receptor reduces allodynia and hyperalgesia in rodent neuropathic pain models. The role of LPAR1 in pain in species other than rodents has not been explored. A model of peripheral neuropathy in nonhuman primates, a species that is phylogenetically closer to humans than rodents, has been developed that demonstrated activation of brain regions associated with pain perception following peripheral stimulation. Thus, the current study examined the effect of PIPE-791, a novel, brain penetrant LPAR1 antagonist, on evoked brain activation in a nonhuman primate model of peripheral neuropathy.

Methods

Brain activation was assessed in cynomolgus macaques (Macaca fascicularis) with a constriction injury (CCI) of the right sciatic nerve utilizing functional magnetic resonance imaging (fMRI). Under anesthesia, the right sciatic nerve at the mid-thigh level of five macaques was loosely ligated with a short length of PVC tubing. Macaques were deeply sedated with propofol during brain imaging with a 1.5 T GE Healthcare MRI. Activation was evoked with von Frey filaments applied to the plantar foot. Two weeks following CCI, PIPE-791 was dosed p.o., 10 mg/kg, once daily, for 28 days. Brain activation was evaluated before CCI and then two, six and eight weeks following CCI.

Results

Prior to CCI, no brain activation was observed during foot stimulation with von Frey filaments. Two weeks following CCI, mechanical stimulation of the foot ipsilateral to CCI led to significant activation of the contralateral insular cortex/secondary somatosensory cortex (Ins/SII) and anterior cingulate cortex (ACC). Contralateral Ins/SII and contralateral thalamus were activated six weeks after CCI (and one day after the last dose of PIPE-791). However, Ins/SII activation was reduced compared to activation observed two weeks after CCI. Also, ACC activation was qualitatively reduced compared to activation observed at two weeks after CCI. Eight weeks after CCI, and 14 days after the last dose of PIPE-791, significant activation was observed of the ACC, contralateral Ins/SII and both contralateral and ipsilateral thalamus.

Conclusions

Based on suppression of brain regions mediating pain intensity and pain affect in a nonhuman primate model of peripheral neuropathy, the current neuroimaging findings support the notion that LPAR1 block leads to antinociception. The current findings also suggest blocking neuroinflammation as a novel mechanism of reducing neuropathic pain. Further studies are needed to assess whether suppression of peripheral or central LPAR1 is crucial for antinociceptive efficacy.

References

Hama et al., Mol. Pain, 2021.

Presenting Author

Aldric Hama

Poster Authors

Aldric Hama

Lead Author

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Karin Stebbins

BSci

Contineum Therapeutics

Lead Author

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Chris Baccei

BS

Contineum Therapeutics

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Dan Lorrain

PhD

Contineum Therapeutics

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Austin Chen

PhD

Contineum Therapeutics

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Takahiro Natsume

PhD

Hamamatsu Pharma Research

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