| The expression and function of opioid and cannabinoid receptors are altered during neuropathic pain. Most studies thus far have examined changes in these receptors in peripheral sensory neurons (primary afferents and DRGs) and in spinal cord, as peripheral sensory signals are initiated through these circuits. However, neuropathic pain is also associated with neuroplastic changes in supraspinal brain regions, leading to enhanced anxiety, altered impulse control, and activation of analgesia via descending pain inhibitory pathways. Exogenous activation of supraspinal opioid and cannabinoid receptors is known to lead to reduced anxiety and antinociception; however, alterations in the expression and function of these receptors during a neuropathic pain state have not been well explored. We examined changes in the expression, function and interaction of these receptors in the cerebral cortex of rats experiencing neuropathic pain. We find that cannabinoid type 1 receptor (CB1R) and delta opioid receptor (DOR) protein levels are increased in the cortex of lesioned animals. However, while CB1R activity is increased, DOR activity is decreased. We hypothesized that this decrease could be due to interactions between these two receptors; this is based on previous in vitro experiments that had shown that these two receptors interact and that this leads to modulation of receptor activity. Using a CB1R-DOR heteromer-specific antibody, we were able to detect increased levels of CB 1R-DOR heteromer protein in the cortex of neuropathic animals. Next, we examined the functionality of these heteromers by testing whether low, non-signaling doses of CB1R ligands influence DOR signaling in cortex. We found that in cortical membranes from neuropathic animals, non-signaling doses of CB1R ligands significantly enhance DOR activity and this is selectively blocked by the heteromer-specific antibody. Together, these results support a role for CB1R-DOR heteromers in altered cortical function of DOR during neuropathic pain and establish allosteric ligand targeting of DOR within CB1R-DOR heteromers as a new approach for therapeutic enhancement of DOR activity. |
