Burn-induced pain is often inadequately managed and its mechanisms, both peripheral and central, are poorly understood. To examine peripheral mechanisms, the effects of full-thickness burns on individual nociceptive fibers in sural nerve of anesthetized rats were studied. Additionally, the study investigated whether topical post-burn treatment with the mu-opioid receptor agonist loperamide ameliorated burn-induced pathologies. Receptive field (RF) properties of C-fibers were determined for 4h before and after producing burns. Burns caused profound tissue damage with edema extending beyond the injury site. Injury located within or proximal to RFs of nociceptors caused rapid decreases in mechanical responsiveness or complete desensitization at the original test site. However, post-burn, RF size frequently grew to include areas of newly sensitized skin. Transient or prolonged periods of ectopic activity was recorded from some nociceptors; this was most prevalent in fibers with RFs proximal to the injury site where burn induced background firing in 60% of the population. In most cases, loperamide significantly increased mechanical thresholds, prevented sensitization of uninjured skin, and reduced discharge.These data indicate that full-thickness burns activate and/or sensitize C-nociceptors, thus probably leading to pain. As loperamide ameliorates nociceptor activation and sensitization, it is an appropriate candidate for burn pain management.