Reduced activation of pain-related brain regions with lysophosphatidic acid receptor subtype-1 antagonist PIPE-791 in a nonhuman primate model of chronic peripheral neuropathy

Abstract

Lysophosphatidic acid (LPA) has been suggested to be a key mediator of painful peripheral neuropathy and blocking its action on LPA receptors could reduce symptoms by decreasing the neuroinflammatory cascade underlying neuropathic pain. The current study examined the effect of PIPE-791, a novel and potent LPA subtype-1 receptor (LPA1R) antagonist which has previously been shown to block demyelination in rodent preclinical models, on regional brain activation in response to non-noxious mechanical stimulation of the foot in male macaques with a unilateral right sciatic nerve injury. Thirteen days after nerve injury, stimuli that did not previously lead to activation in naïve macaques activated the anterior cingulate cortex (ACC) and contralateral insular/secondary somatosensory cortex (Ins/SII). Beginning two weeks after nerve injury, macaques were treated for 28 days with daily oral administration of PIPE-791 by gavage. Six weeks after nerve injury (one day after the last dose of PIPE-791) activation of the contralateral Ins/SII was reduced. Eight weeks after nerve injury (15 days after the last dose), activation of the ipsilateral thalamus, as well as activation of the ACC and contralateral thalamus and Ins/SII was observed. An overall pattern of elevated LPA species following nerve injury and decline with treatment was observed. Evoked brain activation could be related to painful peripheral neuropathy and reduced brain activation could be a direct indicator of reduced pain perception following treatment. The current findings suggest decreasing neuroinflammation by blocking LPA1Rs could be a novel approach to the management chronic painful peripheral neuropathy.

Keywords: Cynomolgus macaque; Demyelination; LPA1 receptor; Neuroinflammation; Neuropathic pain.