Acute Anti-Allodynic Action of Gabapentin in Dorsal Horn and Primary Somatosensory Cortex: Correlation of Behavioural and Physiological Data

Neuropharmacology. 2017 Feb;113(Pt A):576-590. doi: 10.1016/j.neuropharm.2016.11.011. Epub 2016 Nov 14.

Abstract

Neuropathic pain is a debilitating consequence of neuronal injury or disease. Although first line treatments include the alpha-2-delta (α2δ)-ligands, pregabalin and gabapentin (GBP), the mechanism of their anti-allodynic action is poorly understood. One specific paradox is that GBP relieves signs of neuropathic pain in animal models within 30min of an intraperitoneal (IP) injection yet its actions in vitro on spinal dorsal horn or primary afferent neurons take hours to develop. We found, using confocal Ca2+ imaging, that substantia gelatinosa neurons obtained ex vivo from rats subjected to sciatic chronic constriction injury (CCI) were more excitable than controls. We confirmed that GBP (100 mg/kg) attenuated mechanical allodynia in animals subject to CCI within 30min of IP injection.Substantia gelatinosa neurons obtained ex vivo from these animals no longer displayed CCI-induced increased excitability. Electrophysiological analysis of substantia gelatinosa neurons ex vivo suggest that rapidly developing in vivo anti-allodynic effects of GBP i) are mediated intracellularly, ii) involve actions on the neurotransmitter release machinery and iii) depend on decreased excitatory synaptic drive to excitatory neurons without major actions on inhibitory neurons or on intrinsic neuronal excitability. Experiments using in vivo Ca2+ imaging showed that 100 mg/kg GBP also suppressed the response of the S1 somatosensory cortex of CCI rats, but not that of control rats, to vibrotactile stimulation. Since the level of α2δ1 protein is increased in primary afferent fibres after sciatic CCI, we suggest this dictates the rate of GBP action; rapidly developing actions can only be seen when α2δ1 levels are elevated.

Keywords: Alpha 2 delta; Electrophysiology: In vivo calcium imaging; Neuropathic pain; Substantia gelatinosa; Synaptic transmission.

MeSH terms

  • Amines / pharmacology
  • Amines / therapeutic use*
  • Analgesics / pharmacology
  • Analgesics / therapeutic use*
  • Animals
  • Cyclohexanecarboxylic Acids / pharmacology
  • Cyclohexanecarboxylic Acids / therapeutic use*
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Gabapentin
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / physiopathology
  • Male
  • Organ Culture Techniques
  • Pain Measurement / drug effects
  • Pain Measurement / methods*
  • Physical Stimulation / methods
  • Rats
  • Rats, Sprague-Dawley
  • Sciatic Neuropathy / drug therapy
  • Sciatic Neuropathy / physiopathology
  • Somatosensory Cortex / drug effects
  • Somatosensory Cortex / physiology*
  • Spinal Cord Dorsal Horn / drug effects
  • Spinal Cord Dorsal Horn / physiology*
  • gamma-Aminobutyric Acid / pharmacology
  • gamma-Aminobutyric Acid / therapeutic use*

Substances

  • Amines
  • Analgesics
  • Cyclohexanecarboxylic Acids
  • gamma-Aminobutyric Acid
  • Gabapentin