In recent years, cannabinoids have emerged as attractive alternatives or supplements to therapy for chronic pain states. However, in humans the activation of cannabinoid receptors in neurons of the central nervous system is associated with psychotropic side effects, temporary memory impairment and dependence, which arise via the effects of cannabinoids on forebrain circuits. For clinical exploitation of the analgesic properties of cannabinoids, a major challenge is to devise strategies that reduce or abolish their adverse effects on cognitive, affective and motor functions without attenuating their analgesic effects. The cannabinoid receptor family currently includes two cloned metabotropic receptors: CB1, CB2 and possibly GPR55 which are distributed widely across many key loci in pain-modulating pathways, including the peripheral terminals of primary afferents. Modulation of transducer ion channels expressed at nociceptive terminals occurs upon activation of metabotropic cannabinoid receptors, but direct cannabinoid action on ion channels involved in sensory transduction or regulation of neuron excitability likely contributes to the peripheral cannabinoid effects.