Antihyperalgesic effects of cannabinoids produced through peripheral and spinal mechanisms

Cannabinoids, the active molecules originally derived from the marijuana plant, are known to produce antinociception and antihyperalgesia in animals. Evidence suggests that at least some of the antinociceptive effects of cannabinoids are due to activation of cannabinoid receptors located on peripheral and spinal cord neurons. However, the antihyperalgesic capability of cannabinoids acting through peripheral and spinal cord mechanisms is not well known. Therefore, the purpose of this thesis was to examine the antihyperalgesic potential of cannabinoids at the site of injury and in the spinal cord and to determine the effects of cannabinoids on the sensitization of neurons involved in processing nociceptive responses. It was hypothesized that activation of peripheral and spinal CB1 receptors could attenuate behavioral hyperalgesia and neuronal sensitization.;Behavioral methods were employed to study the antihyperalgesic effects of cannabinoids. Capsaicin and heat injury models of hyperalgesia were used to assess the antihyperalgesic potential of locally (or peripherally) applied cannabinoids in rats. Local cannabinoid administration attenuated heat hyperalgesia evoked by capsaicin, the active molecule in hot chili peppers, while both heat and mechanical hyperalgesia produced by a cutaneous heat injury were attenuated. Intracellular electrophysiological recordings from dorsal root ganglion neurons assessed the effects of cannabinoids on the cellular excitability of peripheral neurons. Results suggest that cannabinoids decrease the excitability of nociceptive neurons. A decrease in excitability may be one mechanism by which cannabinoids produce antihyperalgesia in the periphery. In additional behavioral experiments, cannabinoids were administered to rats via intrathecal injections. Intrathecal cannabinoid administration prevented capsaicin-evoked heat and mechanical hyperalgesia, but produced no analgesic effects in the uninjured paw. Corresponding electrophysiological studies demonstrated that cannabinoids applied directly to the spinal cord blocked the sensitization to mechanical stimuli that occurs in nociceptive dorsal horn neurons after peripheral capsaicin injection.;Collectively, the studies presented in this thesis support the hypothesis that cannabinoids attenuate hyperalgesia and neuronal sensitization through peripheral and spinal cord mechanisms. Directly targeting cannabinoid receptors on nociceptive neurons in the periphery and spinal cord may alleviate pain while avoiding the side effects caused through actions at cannabinoid receptors in the brain.