Previous research in our laboratory has shown that the spinal cord is capable of a simple form of instrumental learning. Spinally transected rats that receive controllable shock to an extended hindlimb exhibit a progressive increase in flexion duration that reduces net shock exposure. Subjects that receive uncontrollable shock, on the other hand, do not exhibit an increase in flexion duration, and are unable to produce this instrumental response even when they are later tested with controllable shock. This behavioral deficit can also be elicited by intermittent shock to the tail, and as little as 6 minutes of this shock is sufficient to produce a deficit that can last up to 48 hours as shown by Crown, Ferguson, Joynes, and Grau in 2002. Instrumental training has been shown to provide a number of beneficial effects. The instrumental training regimen produces a lasting effect that enables learning when subjects are later tested with a more difficult response criterion. Similarly, instrumental training can provide protection against the deleterious effects of uncontrollable shock as shown by Crown and Grau in 2001. The present study aims to determine the role of brain-derived neurotrophin factor (BDNF) in the beneficial effects of instrumental training. Experiments 1 and 2 examined the role of BDNF in the facilitory effect of instrumental training. Through the inhibition of endogenous BDNF, Experiment 1 showed that BDNF is necessary for the facilitation effect. Experiment 2 demonstrated that exogenous BDNF can produce the facilitation effect in dose-dependent fashion. Experiment 3 showed that the inhibition of BDNF attenuates the protective effect of instrumental training. Likewise, Experiment 4 showed that exogenous BDNF can substitute for instrumental training, and produce this protective effect. Experiment 5 showed that exogenous BDNF can block the development of the deficit when given immediately after uncontrollable shock. Experiment 6 showed that exogenous BDNF can block the expression of the deficit. Taken together, these experiments outline a major role for BDNF in mediating the beneficial effects of instrumental learning in the rat spinal cord.

We utilize a simple instrumental (response-outcome) learning task to measure spinal plasticity in the isolated spinal cord. Peripheral uncontrollable nociceptive input has been shown to disrupt spinal instrumental learning and induce enhance tactile reactivity. In contrast, 1.5mA of continuous shock has been found to induce antinociception and protect spinal plasticity from the detrimental consequences of uncontrollable stimulation. The experiments of this dissertation examined the link between the beneficial effects of continuous stimulation and antinociception. The results replicated previous work examining the protective and antinociceptive effect of 1.5mA of continuous shock (Experiments 1-2). Novel to this research was the inclusion of a lower (0.5mA) intensity continuous stimulation. Results revealed that 0.5mA of continuous shock induced a comparable antinociception to that seen with 1.5mA of continuous shock (Experiment 1). At this lower intensity, however, continuous shock was unable to protect the isolated spinal cord from the detrimental effect of intermittent stimulation (Experiment 2). Further examination revealed that co-administration of intermittent and continuous shock did not affect continuous shockinduced antinociception. This was true at both the higher (1.5mA) and lower (0.5mA) intensities of continuous shock (Experiment 3). When 0.5mA of continuous shock was administered prior to intermittent shock, this intensity of continuous shock was better able to immunize the spinal cord from the induction of the learning deficit than 1.5mA (Experiment 4). Further analysis called into question the link between antinociception and the protective effect of continuous shock, as the beneficial effect of continuous shock outlasted the expression of antinociception (Experiment 5). Moreover, 0.5mA of continuous shock was found to reverse the expression of the learning deficit, when continuous stimulation was given after intermittent shock treatment (Experiment 6). While blocking the induction of antinociception was not sufficient to prevent the immunizing effect of continuous shock, data suggest that the mu opioid receptor is implicated in the beneficial impact of continuous stimulation (Experiments 7 and 8). Endogenous brain derived neurotrophic factor (BDNF) release was also found to play a role (Experiment 9). Moreover, continuous shock was found to down-regulate the expression of early genes implicated in the development of central sensitization, c-fos and c-jun. Finally, we found that while continuous stimulation was detrimental to locomotor recovery after spinal cord injury, the combined treatment of continuous and intermittent shock did not negatively affect recovery (Experiments 11 and 12).

Prior work from our laboratory has shown that the spinal cord is capable of supporting a simple form of instrumental (response-outcome) learning. In a typical experiment, animals are given a spinal transection at the second thoracic vertebra, and tested 24 h after surgery. If animals are given shock when their leg is in a resting position (controllable shock), they quickly learn to maintain the leg in a flexed position, thereby minimizing shock exposure. Animals exposed to shock that is independent of leg position (uncontrollable shock) fail to learn. This learning deficit can be induced by as little as 6 minutes of shock to either limb or to the tail, and lasts for up to 48 h. The aim of this dissertation was to explore whether the deficit shares behavioral features and pharmacological mechanisms similar to those involved in the induction of neuropathic pain. Work within the pain literature has identified a spinal hyperexcitability that is induced by intense stimulation of pain fibers. This phenomenon, known as central sensitization, is characterized by an increase in tactile reactivity (allodynia) that can be induced by shock or peripheral inflammation. Pharmacological findings have revealed that central sensitization depends on the activation of the N-methyl-D-aspartate (NMDA) and group I metabotropic glutamate receptors (mGluRs). Experiment 1 showed that uncontrollable shock induces a tactile allodynia similar to that observed in central sensitization. Experiment 2 showed that peripheral inflammation caused by a subcutaneous injection of formalin generates a dose-dependent deficit. Experiment 3 indicated that the formalin-induced deficit was observed 24 h after delivery of the stimulus. Experiments 4-8 revealed that the NMDA and group I mGluRs are involved in the deficit. The NMDA receptor was found to be necessary (Experiment 4), but only sufficient to induce a deficit at neurotoxic doses (Experiment 5). Both of the group I mGluRs (subtypes, mGluR1 and mGluR5) were found to be necessary (Experiments 6 & 7). A general group I mGluR agonist summated with a subthreshold intensity of shock to produce a robust deficit (Experiment 8), suggesting shock and mGluR activation produce a deficit through a common mechanism.

Prior work from our laboratory has shown that the spinal cord is capable of supporting a simple form of instrumental (response-outcome) learning. In a typical experiment, animals are given a spinal transection at the second thoracic vertebra, and tested 24 h after surgery. If animals are given shock when their leg is in a resting position (controllable shock), they quickly learn to maintain the leg in a flexed position, thereby minimizing shock exposure. Animals exposed to shock that is independent of leg position (uncontrollable shock) fail to learn. This learning deficit can be induced by as little as 6 minutes of shock to either limb or to the tail, and lasts for up to 48 h. The aim of this dissertation was to explore whether the deficit shares behavioral features and pharmacological mechanisms similar to those involved in the induction of neuropathic pain. Work within the pain literature has identified a spinal hyperexcitability that is induced by intense stimulation of pain fibers. This phenomenon, known as central sensitization, is characterized by an increase in tactile reactivity (allodynia) that can be induced by shock or peripheral inflammation. Pharmacological findings have revealed that central sensitization depends on the activation of the N-methyl-D-aspartate (NMDA) and group I metabotropic glutamate receptors (mGluRs). Experiment 1 showed that uncontrollable shock induces a tactile allodynia similar to that observed in central sensitization. Experiment 2 showed that peripheral inflammation caused by a subcutaneous injection of formalin generates a dose-dependent deficit. Experiment 3 indicated that the formalin-induced deficit was observed 24 h after delivery of the stimulus. Experiments 4-8 revealed that the NMDA and group I mGluRs are involved in the deficit. The NMDA receptor was found to be necessary (Experiment 4), but only sufficient to induce a deficit at neurotoxic doses (Experiment 5). Both of the group I mGluRs (subtypes, mGluR1 and mGluR5) were found to be necessary (Experiments 6 & 7). A general group I mGluR agonist summated with a subthreshold intensity of shock to produce a robust deficit (Experiment 8), suggesting shock and mGluR activation produce a deficit through a common mechanism.