There are several interesting findings in the present study that sought to identify the role of BDNF in the incisional pain. First, hind-paw incision induced transient activation of BDNF expression, mainly localized in the nerve terminals and neurons in the lumbar DRG and spinal cord; Second, the increased BDNF expression was changed to large-sized neurons from the small-sized neurons in the DRG in response to surgical incision; Third, sciatic nerve block by local anesthetic can prevent the upregulated BDNF in the DRG and spinal cord; Finally, IT administration, but not IP administration of anti-BDNF antibody dramatically reduced the mechanical allodynia developed by the incision.
Like inflammatory pain and neuropathic pain, incisional pain also induced the upregulation of BDNF in the DRG and spinal cord in the present study. However, the expression pattern of BDNF in the incisional pain was distinct from those in the inflammatory pain and neuropathic pain. In neuropathic pain, the increased BDNF in the spinal cord was mainly expressed in the activated microglia . On the other hand, in the CFA-induced inflammatory pain model, BDNF expression was considerably increased in the small- and median-sized neurons in the DRG and the axon fibers in the dorsal horns . In the present study, surgical incision induced the activation of BDNF in the large-sized neurons in DRG and the axon fibers and neurons in the dorsal horns indicating a unique BDNF expression in response to surgical incision. The distinct expression pattern of BDNF in these three types of pain strongly indicated that there might be different roles of BDNF in these three types of pain and the incisional pain has a unique mechanism as compared with the other two types of pathological pain. More interestingly, the elevated BDNF level in DRG was also localized in the large-sized neurons although BDNF is normally expressed in the small- and medium-sized neurons. Given that the central fibers of large-sized neurons in DRG mainly project to the deep layers of spinal cord which are closely related to mechanical allodynia, the phenotypic changes of the elevated BDNF in the present study strongly suggest that the activated BDNF is involved in the development of mechanical allodynia after surgical incision.
In the present study, IT injection of BDNF antibody attenuated the mechanical allodynia after incision strongly suggesting that BDNF was implicated in the incision-evoked mechanical allodynia. However, it remains elusive the underlying mechanism that BDNF contributes to the incision-evoked pain hypersensitivity. Ample evidence demonstrated that incision-evoked pain hypersensitivity was mainly mediated by AMPA/kainite-dependent mechanisms, but not NMDA receptor-dependent mechanism. This is because the AMPA antagonist but not NMDA receptor antagonist can reverse the incision-evoked pain hypersensitivity [11–13]. However, the data from mice and rat in vitro spinal cord preparation showed that BDNF led to hyperalgesia via an NMDA-mediated mechanism after peripheral inflammation [3, 20]. Together with previous studies, the present study suggests that BDNF modulate the incision-evoked pain hypersensitivity through non-NMDA receptors such as TrkB or ERK. In this regard, compelling evidence showed that intraspinal injection of BDNF could phosphoryate ERK in the spinal cords, which subsequently activate the downstream signals including the pain-related neurotransmitters  or the related inflammatory mediator, IL-1β.
It has been reported that NGF contributed to the neuropathic pain and inflammatory pain, and was also associated with incision-evoked pain hypersensitivity . The increase of NGF in the subcutaneous tissue after hind-paw incision was coincided with the pain-related behavior, and systemic anti-NGF treatment could reverse the incision-evoked guarding pain, but not mechanical allodynia . In spite of the fact that activation of BDNF was one way that NGF contributed to inflammatory pain [2, 22], BDNF might play the differential roles in the incision-evoked pain hypersensitivity as compared with NGF. In the present study, the fact that IT injection, but not systemic treatment of anti-BDNF antibody reduced the incision-evoked mechanical allodynia strongly indicated that BDNF might be involved in the incision-evoked mechanical allodynia whereas NGF be associated with spontaneous-like pain after incision.
Considerable evidence shows that inflammatory mediators in the spinal cord are activated segmentally in response to surgical incision. It has been reported that bilateral hind paw incision induce mild increase of cyclooxygenas 2 (COX-2) in the lumbar spinal cord but not cervical segments [23, 24]. Our recent study also showed that surgical incision induced the segmental upregulation of IL-1β in the spinal cord . In the present study, incision also induced the increase of BDNF level in the ipsilateral lumbar segments but not that in the contralateral side or thoracic spinal cord suggesting the expression pattern of BDNF level in the spinal cord was similar to that of COX-2 or the cytokines. However, unlike the activated inflammatory mediators which were not affected by the sciatic nerve block [23, 24], the increased BDNF in the DRG or spinal cord could be totally prevented by the sciatic nerve block. These strongly indicate that the underlying mechanisms that incision-mediated the activation of inflammatory mediators and incision-mediated BDNF upregulation in the spinal cord are different. The rapid increase of BDNF in the DRG and spinal cord also rules out the possibility of the retrogradely transport of BDNF from the local injured tissue . The fact that pretreatment of lidocaine completely prevented the upregulation of BDNF after incision indicated that the increased BDNF is through by nerve afferent transmission. In this regard, considerable evidence shows that neuronal depolarization induced by KCL or electrical stimulation of C fibers can induce the sustained increase of BDNF expression in cerebellar granule or sensory neurons [26–28]. In the present study, the increased BDNF is likely from the de nono synthesis in the large-sized neurons in DRG and novel induction in the spinal cord due to the activated burst of firing from the sensitized nerve endings in the injured tissue. The upregulated BNDF, in turn, may activate downstream signaling and contribute to the development of mechanical allodynia following incision.
In the present study, the IT injection but not IP injection of anti-BDNF antibody substantially inhibited incision-evoked mechanical allodynia suggesting that the spinal BDNF may play more important role for the incision-evoked pain hypersensitivity. Thus, blocking the upregulated spinal BDNF may be a novel potential therapeutic approach to treat post-operative pain. It has been well known that alleviation of the post-operative pain, on the other hand, can reduce the anxiety and provide subjective comfort, and should also blunt the autonomic and somatic reflex response and thus restore organ functions and enable mobilization and food intake, thereby helping to improve the outcome. Multimodal analgesia has been suggested to treat post-operative pain in which combination of different modalities, working at different pain mechanisms and reduce the side effect. In this regard, the opioids, paracetamol, NSAIDs, and COX-2 inhibitors are widely used as the pharmaceutical interventions to treat pain . In the present study, the mechanism of incision-mediated BDNF may be different from that of upregulated COX-2 or cytokine induced by incision. It still remains to be determined whether BDNF antagonist (or inhibitor) can interact with other analgesia or not. However, the fact that neutralizing the increased BDNF induced by incision can reduce the mechanical allodynia following incision strongly suggest that inhibiting BDNF may be a new approach in the multimodal analgesia to treat post-operative pain.