Abstract
Therapeutic strategies targeting phantom limb pain (PLP) provide inadequate pain relief; therefore, a robust and clinically relevant animal model is necessary. Animal models of PLP are based on a deafferentation injury followed by autotomy behavior. Clinical studies have shown that the presence of pre-amputation pain increases the risk of developing PLP. In the current study, we used Sprague-Dawley male rats with formalin injections or constriction nerve injury at different sites or time points prior to axotomy to mimic clinical scenarios of pre-amputation inflammatory and neuropathic pain. Animals were scored daily for PLP autotomy behaviors, and several pain-related biomarkers were evaluated to discover possible underlying pathological changes. Majority displayed some degree of autotomy behavior following axotomy. Injury prior to axotomy led to more severe PLP behavior compared to animals without preceding injury. Autotomy behaviors were more directed toward the pretreatment insult origin, suggestive of pain memory. Increased levels of IL-1β in cerebrospinal fluid and enhanced microglial responses and the expression of NaV1.7 were observed in animals displaying more severe PLP outcomes. Decreased expression of GAD65/67 was consistent with greater PLP behavior. This study provides a preclinical basis for future understanding and treatment development in the management of PLP.
Highlights
Amputations due to trauma or medical conditions often lead to the development of phantom sensations, perceived as they originate from the missing body part
phantom limb pain (PLP)-like behavior was induced in rats by axotomy of the sciatic/saphenous nerves, preceded by formalin injection or constriction of the nerve, to mimic clinical scenarios of peripheral tissue damage in complex injuries prior to medically indicated amputation
Most animals displayed some degree of autotomy behavior following axotomy that has been considered indicative of dysesthetic pain in animal models [13,14,15,16,17,18], and may be useful as an approximation of PLP sensations in humans
Summary
Amputations due to trauma or medical conditions often lead to the development of phantom sensations, perceived as they originate from the missing body part. Phantom limb pain (PLP), a perception of pain from the missing extremities, is notoriously difficult to manage and can significantly impact the productivity and quality of life. The majority of amputees (50–85%) suffer from persistent or intermittent pain sensations associated with the limb that has been removed, which is often debilitating (reported as severe pain in over 30%), and interferes with daily activity, rehabilitation therapies, and utilization of prosthetic limb devices [1,2,3,4,5]. Despite the high prevalence and severity of PLP in amputees, mechanisms underlying PLP are poorly understood and current therapeutic options are mostly only marginally effective. Aberrant contributing peripheral and central neural processes that have gained consensus as proposed mechanisms include a likely progression from peripheral neuroma formation, to dorsal horn inflammation and disinhibition, and later cortical reorganization [6,7,8,9,10,11,12]
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