One in three Americans suffer from chronic pain. Available therapeutic interventions show limited efficacy and are plagued by adverse side effects (e g, altered mental status, sedation, nausea) that accompany systemic routes of drug administration Novel pharmacotherapies that specifically target the periphery therefore represent an alternative strategy for managing pain in the absence of unwanted central side-effects. Activation of a cannabinoid system- a nonopioid system that acts through a marijuana-like mechanism- in the periphery attenuates nociceptive responding The proposed research combines correlative behavioral and neurophysiological approaches to examine the functional consequences of peripheral cannabinoid actions on nociceptive transmission in vivo The use of subtype selective competitive antagonists and high affinity agonists provide the pharmacological tools required to study peripheral cannabinoid actions The proposed work uses a rat model of inflammation to test the hypothesis that a peripheral cannabinoid mechanism suppresses responses evoked by natural cutaneous stimulation in physiologically identified neurons of the spinothalamic tract Behavioral correlates for the electrophysiological studies will be established by assessing peripheral cannabinoid modulation of responsiveness to thermal and punctate mechanical stimulation under similar conditions The consequences of peripheral inflammation on axonal transport of cannabinoid receptors to peripheral nerve terminals is evaluated The development of effective pharmacotherapies for pain that are non-toxic, non-addicting and devoid of side-effects is likely to have a profound impact by improving quality of human life and reducing socioeconomic costs associated with inadequate pain management.