Neuronal hyperactivity at the spinal cord and periaqueductal grey during painful diabetic neuropathy: Effects of gabapentin

Abstract

Painful diabetic neuropathy may be due to impairments in descending modulation of nociceptive transmission at the spinal cord. In the present study, streptozotocin diabetic rats (STZ rats) with neuropathic symptoms (mechanical hypersensitivity) were used to perform a time-course evaluation of neuronal activity at the spinal dorsal horn and at the periaqueductal grey matter (PAG), a major brainstem area of pain modulation. The expression of Fos protein, a marker of nociceptive activation, progressively increased at the spinal dorsal horn at 4 and 10 weeks. At the PAG, increases in Fos expression were detected until the 4th week, with a reversal to baseline values at 10 weeks in all areas except the ventrolateral PAG. Co-localisation of Fos with NeuN ascertained the neuronal nature of Fos-expressing cells at the spinal cord and PAG. Four weeks after diabetes induction, the effects of gabapentin (i.p. injection of 50mg/kg, daily during 3 days) were assessed. Gabapentin decreased Fos expression at the spinal cord and PAG and reversed mechanical hypersensitivity. The present study shows that diabetic neuropathy is accompanied by a progressive increase of the spontaneous neuronal activity at the spinal cord. Changes in descending modulation of nociceptive transmission from the PAG are likely to occur during diabetic neuropathy, probably with exacerbation of facilitatory actions. The effects of gabapentin in reversing the behavioural signs of diabetic neuropathy and neuronal hyperactivity in the spinal cord and PAG reinforce the central causes of diabetic neuropathy and point to the central targets of the drug.

Blocking mammalian target of rapamycin (mTOR) improves neuropathic pain evoked by spinal cord injury

“…mTOR, S6K1, and 4E-BP1 are expressed in the mammalian nervous system, particularly in spinal cord dorsal horn [7, 22]. Because the superficial dorsal horn is the first synaptic site from peripheral afferent nerves to the central nervous system[23, 24] and plays an important role in modulating pain and morphine tolerance [12, 25], in this study we determined the role played by mTOR in the superficial dorsal horn in regulating mechanical and thermal hyperalgesia following development of SCI.…”

Insights into the pathogenesis and treatment of painful diabetic neuropathy

“…Decreases in activation of the PAG and the habenular nuclei in a streptozotocin model of diabetic neuropathy in Sprague-Dawley rats, using autoradiography, have been reported, suggesting that there may be a deactivation of this endogenous pain-relieving area in diabetic neuropathic pain (Paulson et al, 2007). Neuronal markers of nociception were increased in the periaqueductal gray in streptozotocin rats with signs of neuropathic pain and were downregulated during effective pain relief provided by gabapentin (Morgado et al, 2010), pointing towards a pathologic failure of inhibition in diabetic painful neuropathy.…”

Blocking Mammalian Target of Rapamycin (mTOR) Alleviates Neuropathic Pain Induced by Chemotherapeutic Bortezomib

“…The superficial dorsal horn is the first synaptic site from peripheral afferent nerves to the central nervous system [13,14] and plays an important role in modulating pain [15,16]. Especially, the superficial dorsal horn at the lumbar levels (i.e., L5 to L6) is the first synaptic site receiving pain inputs from the hind paw.…”