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

• Published in: European journal of pain Vol. 14; no. 7; pp. 693 - 699
• Main Authors: Morgado, Carla, Terra, Patrícia Pereira, Tavares, Isaura
• Format: Journal Article
• Language: English
• Published: Oxford, UK Elsevier Ltd 01-08-2010; Blackwell Publishing Ltd
• Subjects: Amines - pharmacology; Amines - therapeutic use; Analgesics - pharmacology; Analgesics - therapeutic use; Analysis of Variance; Anesthesia & Perioperative Care; Animals; c-fos; Cyclohexanecarboxylic Acids - pharmacology; Cyclohexanecarboxylic Acids - therapeutic use; Descending modulation; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetic Neuropathies - drug therapy; Diabetic Neuropathies - metabolism; Diabetic Neuropathies - physiopathology; gamma-Aminobutyric Acid - pharmacology; gamma-Aminobutyric Acid - therapeutic use; Hyperalgesia; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Hyperalgesia - physiopathology; Male; Neurons - drug effects; Neurons - physiology; PAG; Pain Medicine; Periaqueductal Gray - drug effects; Periaqueductal Gray - metabolism; Periaqueductal Gray - physiopathology; Proto-Oncogene Proteins c-fos - metabolism; Rats; Rats, Wistar; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - physiopathology; STZ diabetic rats; c-fos; STZ diabetic rats; Descending modulation; PAG; Hyperalgesia
• ISSN: 1090-3801; 1532-2149
• DOI: 10.1016/j.ejpain.2009.11.011

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 50 mg/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.