Early endogenous activation of CB1 and CB2 receptors after spinal cord injury is a protective response involved in spontaneous recovery

PLoS One. 2012;7(11):e49057. doi: 10.1371/journal.pone.0049057. Epub 2012 Nov 13.

Abstract

Spinal cord injury (SCI) induces a cascade of processes that may further expand the damage (secondary injury) or, alternatively, may be part of a safeguard response. Here we show that after a moderate-severe contusive SCI in rats there is a significant and very early increase in the spinal cord content of the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (anandamide, AEA). Since 2-AG and AEA act through CB1 and CB2 cannabinoid receptors, we administered at 20 minutes after lesion a single injection of their respective antagonists AM281 and AM630 alone or in combination to block the effects of this early endocannabinoid accumulation. We observed that AM281, AM630 or AM281 plus AM630 administration impairs the spontaneous motor recovery of rats according to the Basso-Beattie-Bresnahan (BBB) locomotor scale. However, blockade of CB1, CB2 or both receptors produced different effects at the histopathological level. Thus, AM630 administration results at 90 days after lesion in increased MHC-II expression by spinal cord microglia/monocytes and reduced number of serotoninergic fibres in lumbar spinal cord (below the lesion). AM281 exerted the same effects but also increased oedema volume estimated by MRI. Co-administration of AM281 and AM630 produced the effects observed with the administration of either AM281 or AM630 and also reduced white matter and myelin preservation and enhanced microgliosis in the epicentre. Overall, our results suggest that the endocannabinoids acting through CB1 and CB2 receptors are part of an early neuroprotective response triggered after SCI that is involved in the spontaneous recovery after an incomplete lesion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endocannabinoids / metabolism
  • Gliosis / complications
  • Gliosis / pathology
  • Gliosis / physiopathology
  • Locomotion
  • Lumbar Vertebrae / pathology
  • Lumbar Vertebrae / physiopathology
  • Magnetic Resonance Imaging
  • Male
  • Microglia / metabolism
  • Microglia / pathology
  • Motor Activity / drug effects
  • Myelin Sheath / metabolism
  • Myelin Sheath / pathology
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Recovery of Function*
  • Serotonergic Neurons / metabolism
  • Serotonergic Neurons / pathology
  • Spinal Cord Injuries / metabolism
  • Spinal Cord Injuries / pathology
  • Spinal Cord Injuries / physiopathology*
  • Spinal Cord Injuries / prevention & control*
  • Temperature

Substances

  • Endocannabinoids
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2

Grant support

This work was supported by grants from Spanish Ministerio de Ciencia e Innovación (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III; 08/1999), from Gobierno de Castilla-La Mancha (Fundación para la Investigación Sanitaria en Castilla-La Mancha; FISCAM 2008/37) and from Fundación Mutua Madrileña. SOG is a Ramón y Cajal Scholar funded by Spanish Ministerio de Ciencia e Innovación (MICINN, SAF2010-22198-C02-01) and Comunidad Autónoma de Madrid (P2010/BMD-2353). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.