Neuronal and glial localization of the cannabinoid‐1 receptor in the superficial spinal dorsal horn of the rodent spinal cord

Abstract

A long line of experimental evidence indicates that endogenous cannabinoid mechanisms play important roles in nociceptive information processing in various areas of the nervous system including the spinal cord. Although it is extensively documented that the cannabinoid-1 receptor (CB(1)-R) is strongly expressed in the superficial spinal dorsal horn, its cellular distribution is poorly defined, hampering our interpretation of the effect of cannabinoids on pain processing spinal neural circuits. Thus, we investigated the cellular distribution of CB(1)-Rs in laminae I and II of the rodent spinal dorsal horn with immunocytochemical methods. Axonal varicosities revealed a strong immunoreactivity for CB(1)-R, but no CB(1)-R expression was observed on dendrites and perikarya of neurons. Investigating the co-localization of CB(1)-R with markers of peptidergic and non-peptidergic primary afferents, and axon terminals of putative glutamatergic and GABAergic spinal neurons we found that nearly half of the peptidergic (immunoreactive for calcitonin gene-related peptide) and more than 20% of the non-peptidergic (binding isolectin B4) nociceptive primary afferents, more than one-third and approximately 20% of the axon terminals of putative glutamatergic (immunoreactive for vesicular glutamate transporter 2) and GABAergic (immunoreactive for glutamic acid decarboxylase; GAD65 and/or GAD67) spinal interneurons, respectively, were positively stained for CB(1)-R. In addition to axon terminals, almost half of the astrocytic (immunoreactive for glial fibrillary acidic protein) and nearly 80% of microglial (immunoreactive for CD11b) profiles were also immunolabeled for CB(1)-R. The findings suggest that the activity-dependent release of endogenous cannabinoids activates a complex signaling mechanism in pain processing spinal neural circuits into which both neurons and glial cells may contribute.

Dynamic changes to the endocannabinoid system in models of chronic pain

“…Cannabinoid receptor expression is upregulated in the spinal cord; however, the exact location is not yet clear. CB1 receptors are also present on astrocytes [31], while CB2 receptors are present on microglia [32] and are thought to be upregulated on pre-synaptic terminals [33] following nerve injury. Spinal administration of CB2 receptor agonists inhibits responses of WDR neurons and thus an increase in postsynaptic expression of CB2 receptors cannot be ruled out.…”

The Effects of Peptide and Lipid Endocannabinoids on Arthritic Pain at the Spinal Level

“…[25][26][27] As far as the spinal level is concerned, we are the first to show its antinociceptive potency, and that the effect is reversed by a CB 1 antagonist drug (but not by a CB 2 antagonist), suggesting that the antiallodynic effect of 2-AG is mainly attributable to the activation of CB 1 receptors at the spinal level. CB 1 receptors, the molecular targets of 2-AG, are located on primary afferent fiber endings and/or on intrinsic interneurons in the dorsal horn of the spinal cord 47,48 ; therefore, their activation could have led to the observed antinociception. It is important to consider that these ligands can influence the activity of neurons in DRG too, because the CB receptors can be found on DRG neurons, 49,50 and it has been shown that intrathecal injection of sodium fluorescein results in massive staining in the DRG both in the cellular and fiber portions.…”

The Cannabinoid 1 Receptor and Progenitor Cells in the Adult Central Nervous System

“…In the spinal cord, several studies have been published demonstrating that CB1R is found throughout the gray matter, but at higher densities in the dorsal areas relative to the ventral areas (Herkenham, Lynn et al 1991;Tsou, Brown et al 1998;Ong and Mackie 1999;Farquhar-Smith, Egertova et al 2000;Mackie 2005;Hegyi, Kis et al 2009). Many of our essential functions depend on an intact and healthy spinal cord, such as sensation (modulated primarily by the dorsal spinal cord) and locomotion (modulated primarily by the ventral spinal cord).…”