Activation of spinal cannabinoid (1) receptors inhibits C-fibre driven hyperexcitable neuronal responses and increases [S-35]GTP gamma S binding in the dorsal horn of the spinal cord of noninflamed and inflamed rats

The analgesic potential of cannabinoid (CB) receptor agonists is of clinica l interest. Improved understanding of the mechanisms of action of cannabino ids at sites involved in the modulation of acute and sustained inflammatory nociceptive transmission, such as the spinal cord, is essential. In vivo e lectrophysiology was used to compare the effect of the synthetic CB agonist , HU210, on acute transcutaneous electrical-evoked responses of dorsal horn neurons of noninflamed anaesthetized rats and anaesthetized rats with a pe ripheral carrageenin inflammation. CB receptor G-protein coupling in lumbar spinal cord sections of noninflamed and carrageenin-inflamed rats was stud ied with in vitro autoradiography of guanylyl 5'-[gamma-[S-35]thio]triphosp hate ([S-35]GTP gamma S) binding. Spinal HU210 significantly inhibited the C-fibre-mediated late (300-800 ms) postdischarge response of dorsal horn ne urons of noninflamed and carrageenin-inflamed rats; the CB1 receptor antago nist SR141716A blocked the effect of HU210. HU210 had limited effects on A- fibre-evoked dorsal horn neuronal responses of both groups of rats. HU210 s ignificantly increased [S-35]GTP gamma S binding in the dorsal horn of the spinal cord of both groups of rats compared with basal [S-35]GTP gamma S bi nding; SR141716A blocked these effects. The predominant effect of spinal HU 210, via CB1 receptor activation, was on the C-fibre driven postdischarge r esponses, a measure of neuronal hyperexcitability following repetitive C-fi bre stimulation. Sustained, but not enhanced, antinociceptive effects of HU 210 following carrageenin inflammation are reported; CB receptor G-protein coupling was not altered by inflammation. These results strengthen the body of evidence suggesting CB agonists may be an important novel analgesic app roach for the treatment of sustained pain states.