Pioglitazone rapidly reduces neuropathic pain through astrocyte and nongenomic PPARγ mechanisms

Abstract

Repeated administration of peroxisome proliferator-activated receptor gamma (PPARγ) agonists reduces neuropathic pain-like behavior and associated changes in glial activation in the spinal cord dorsal horn. As PPARγ is a nuclear receptor, sustained changes in gene expression are widely believed to be the mechanism of pain reduction. However, we recently reported that a single intrathecal injection of pioglitazone, a PPARγ agonist, reduced hyperalgesia within 30 minutes, a time frame that is typically less than that required for genomic mechanisms. To determine the very rapid anti-hyperalgesic actions of PPARγ activation we administered pioglitazone to rats with spared nerve injury (SNI) and evaluated hyperalgesia. Pioglitazone inhibited hyperalgesia within 5 min of injection, consistent with a non-genomic mechanism. Systemic or intrathecal administration of GW9662, a PPARγ antagonist, inhibited the anti-hyperalgesic actions of intraperitoneal or intrathecal pioglitazone, suggesting a spinal PPARγ-dependent mechanism. To further address the contribution of non-genomic mechanisms, we blocked new protein synthesis in the spinal cord with anisomycin. When co-administered intrathecally, anisomycin did not change pioglitazone anti-hyperalgesia at an early 7.5 min timepoint, further supporting a rapid non-genomic mechanism. At later timepoints anisomycin reduced pioglitazone anti-hyperalgesia, suggesting a delayed recruitment of genomic mechanisms. Pioglitazone reduction of SNI-induced increases in GFAP expression occurred more rapidly than expected, within 60 min. We are the first to show that activation of spinal PPARγ rapidly reduces neuropathic pain independent from canonical genomic activity. We conclude that acute pioglitazone inhibits neuropathic pain in part by reducing astrocyte activation, and via both genomic and non-genomic PPARγ mechanisms.

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

“…Further studies are needed to investigate the differential effect of pioglitazone on heat and noxious mechanical sensitivity. In addition, we speculate that pioglitazone would reduce cold hypersensitivity as we recently reported that pioglitazone reduced the development of 63 and reversed 30 hyperresponsivitiy to acetone in the spared nerve injury model of neuropathic pain.…”

“…First, spinal sites are rich in PPARγ expression 11, 55, 61 and pioglitazone crosses the blood-brain barrier 56 . Second, intrathecal administration of PPARγ antagonists inhibits the antihyperalgesic effect of both repeated systemic or single intrathecal administration of PPARγ agonists 11, 30, 63 . Alternatively, non-PPARγ mechanisms can be proposed for the antihyperalgesic effects of pioglitazone in PDN.…”

“…This is based on several lines of evidence. First, pioglitazone and other PPARγ agonists reduce neuropathic pain-like behavior in normoglycemic animals after various routes of administration including: repeated oral 55, 63 or intraperitoneal 31, 55, 63, 96 ; local injection to the injured sciatic nerve 96 or incised paw 31 ; or a single spinal 11, 30, 62, 71 or brain 62 injection. Second, numerous drugs can reduce PDN without reducing hyperglycemia in patients with PDN, including tapentadol 88 or the FDA-approved PDN medications duloxetine and pregabalin 59, 90 .…”

“…TZDs also reduce the molecular and behavioral sequelae of neurological disease 22, 40 , as well as neuropathic pain associated with brain 84, 111 , spinal cord 58, 71 or nerve 11, 30, 55, 63, 96 injury. For example, we recently reported that pioglitazone reduced hypersensitivity to non-noxious mechanical stimulation in rats with traumatic nerve injury 63 .…”

Activity-triggered tetrapartite neuron–glial interactions following peripheral injury

“…Ample evidence supports a role of astrocytes in the development of persistent pain hypersensitivity after injury [41-43]. Inhibition of astrocyte activity has been associated with the antihyperalgesic effect of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist [44]. Direct nerve stimulation induced astroglial activity and cytokine release [45] and prolonged local anesthesia block of afferent neurons delayed the onset of pain-related behavior and reduced nerve injury-induced astrocytic responses [46], indicating that astrocytic response is regulated by neural input.…”