- Email: [email protected]
Neural effects of systemic lidocaine on chronic neuropathic pain patients
Abstracts
The Journal of Pain
E11 Functional Brain Imaging (252) Neural effects of systemic neuropathic pain patients
P39
E12 Hyperalgesia/Allodynia lidocaine
on
chronic
H Ung, S Mackey, N Chatterjee, M Tieu, R Moericke, and I Carroll; Stanford University, Stanford, CA Millions of Americans with neuropathic pain also present with mechanical allodynia, in which normally innocuous stimuli elicits pain. Sodium channel blockers such as lidocaine have shown efficacy in attenuating the painful sensation, though the specific changes that occur within the central nervous system remain ambiguous. This study aims to elucidate the mechanism of analgesic response prompted by systemic lidocaine through the use of functional magnetic resonance imaging (fMRI). Chronic pain patients (N = 8) with mechanical allodynia provided written and informed consent according to protocols approved by the Stanford Institutional Review Board. Functional MRI scans were conducted at a Stanford University 3 Tesla GE scanner using a standard block design where the stimulus was brushing of the allodynic area under 3 conditions: baseline, saline placebo, and lidocaine. Brushing of an unaffected area under baseline conditions was used as a control. A fixed effects, general linear model analysis was performed using SPM8. We found increased activity in prefrontal areas and decreased activity in the amygdala and hippocampal regions in conditions of lidocaine versus placebo. In addition, systemic lidocaine reduced activity in the primary sensory cortex, supplemental motor area, and putamen. Although lidocaine is a nonspecific sodium channel blocker and sodium channels are ubiquitous throughout the nervous system, these results indicate that lidocaine influences specific regions of the brain. The exact mechanism remains unclear, and further analysis and data are required to improve our understanding of the analgesic effects of lidocaine.
(254) Antinociceptive effect of recombinant neuroprogenitor intraspinal transplants in models of peripheral and central neuropathic pain S Jergova, M Varghese, D Collante, S Bartley, S Gajavelli, and J Sagen; University of Miami, Miami Project, Miami, FL Hypothesized mechanisms underlying chronic neuropathic pain following injury to the peripheral or central nervous system include increased hyperexcitability of spinal dorsal horn neurons due to loss or dysfunction of inhibitory g-aminobutyric acid (GABA)-ergic interneurons, and enhanced excitatory glutamate signaling through NMDA receptors. Restoration of inhibitory tone and/ or reduction of hyperexcitability via transplantation of selected cell types is a potential long-term intervention. The use of a recombinant neuronal progenitor cell (NPC) approach targeting GABA and glutamatergic signaling was evaluated in these experiments. Pre-differentiated rat GABAergic NPCs were intraspinally injected into rats with peripheral nerve injury-induced pain using sciatic nerve injury model. An improvement in behavioral outcome was observed for mechanical hyperalgesia and cold allodynia. Concurrent intrathecal injection of serine-histogranin (SHG), an NMDA antagonist, enhanced the analgesic effect of grafted cells. In accordance with behavioral data we found decreased number of c-Fos positive neurons in the superficial dorsal horn laminae in SHG treated rats, suggesting attenuated injury-induced excitation of nociceptive spinal neurons. For site-specific release of SHG a recombinant NPC capable of releasing GABA and SHG were engineered and intraspinally transplanted into rats after peripheral nerve injury. An markedly enhanced attenuation of cold allodynia and modestly attenuated mechanical hyperalgesia were observed. Intraspinal injection of GABAergic NPC was also used in the clip compression model of below-level pain after spinal cord injury. Beneficial effects in reducing tactile and cold allodynia were observed for several weeks post grafting. Our results suggest that transplantation of GABAergic NPC can attenuate peripheral and central nerve injury-induced chronic pain and that enhancement of this approach could be achieved by genetic modification of grafted cells. Supported by NS51667.
(253) How does physical activity relate to cognitive pain modulation in women?
(255) Morphine induces pain behavior and iGluR4 upregulation in murine spinal cord
M Shields, L Ellingson, A Stegner, and D Cook; University of Wisconsin-Madison, Madison, WI
A Baker, S Zhou, G Hargett, J Moron-Concepcion, and S Carlton; University of Texas Medical Branch, Galveston, TX
Fibromyalgia (FM) has been conceptualized as a disorder of the central nervous system (CNS), characterized by augmented sensory processing and an inability to effectively modulate pain. We previously reported that physical activity (PA) is related to brain processing of pain, providing preliminary evidence for a potential mechanism of pain management through exercise. The purpose of this study was to extend our previous work and examine whether PA was related to pain modulation. Thirty-six women (16 FM and 20 Control) completed self-report and accelerometer measures of PA and underwent functional magnetic resonance imaging of painful heat, administered alone and during a distracting cognitive task. For healthy controls, accelerometer data were significantly (p<0.005) and positively related to brain responses to pain during the cognitive task in regions often implicated in pain modulation (left anterior and posterior insula, right anterior insula, right dorsal and ventral lateral prefrontal and right orbital frontal cortices (r2=0.60). Significant (p<0.005) negative relationships occurred in left lateral prefrontal, left dorsolateral prefrontal and left middle frontal cortices (r2=0.61). Self-reported PA was positively related (p<0.05) to right orbital frontal cortex (r2=0.56) activity and changes in pain ratings due to the distracting cognitive task (r2=0.25). For FM patients, accelerometer data were negatively (p<0.005) related to activity in the left orbital frontal, and right and left inferior medial frontal cortices (r2=0.77). No significant relationships were found for self-reported PA and brain responses to pain during the cognitive task in FM patients and neither self-reported nor accelerometer measures were related to changes in pain ratings due to the distracting cognitive task. These preliminary results support a role for PA in pain modulation for healthy controls, but not FM patients. Experiments designed to increase PA levels may help further understand how exercise can be used to effectively treat FM. Supported by a grant from NIAM/NIH AR50969.
Studies highlight AMPA receptors (AMPAR) in morphine-induced dependence and withdrawal. Marked changes in AMPAR expression occur in the hippocampus of mice treated with morphine for two days every 12 hr. Using the same morphine injection paradigm, our study investigates morphine-induced pain behaviors and changes in AMPAR expression in the spinal cord. Mice received morphine (5, 8, 10, and 15 mg/kg, i.p.) or saline (n = 9-10/group) over 2 days, every 12 hr. Morphine-treated mice showed: a) mechanical allodynia at 12hr and 6 days post-morphine, b) cold allodynia (-5 C61 C) at 12 hr only and c) no heat hyperalgesia (46 C60.5 C). Immunostaining for AMPA iGluR4 in the spinal cord showed increases in lamina (L) III-V in morphine-treated mice 6 days post morphine treatment. The behavioral sensitization may reflect changes in expression/function of TRPM8 and/or TRPA1 receptors, which are implicated in cold-mechanical sensitivity. NK-1 receptor-expressing projection neurons in LIII-V are strongly labeled for iGluR41 and receive input from nociceptors. Upregulation of iGluR4 suggests enhanced synaptic input from nociceptors to these cells, and this could be one mechanism producing mechanical and cold sensitivity. Work was supported by NS027910 and DA027460. (Todd, EJN 2009)
The Journal of Pain
E11 Functional Brain Imaging (252) Neural effects of systemic neuropathic pain patients
P39
E12 Hyperalgesia/Allodynia lidocaine
on
chronic
H Ung, S Mackey, N Chatterjee, M Tieu, R Moericke, and I Carroll; Stanford University, Stanford, CA Millions of Americans with neuropathic pain also present with mechanical allodynia, in which normally innocuous stimuli elicits pain. Sodium channel blockers such as lidocaine have shown efficacy in attenuating the painful sensation, though the specific changes that occur within the central nervous system remain ambiguous. This study aims to elucidate the mechanism of analgesic response prompted by systemic lidocaine through the use of functional magnetic resonance imaging (fMRI). Chronic pain patients (N = 8) with mechanical allodynia provided written and informed consent according to protocols approved by the Stanford Institutional Review Board. Functional MRI scans were conducted at a Stanford University 3 Tesla GE scanner using a standard block design where the stimulus was brushing of the allodynic area under 3 conditions: baseline, saline placebo, and lidocaine. Brushing of an unaffected area under baseline conditions was used as a control. A fixed effects, general linear model analysis was performed using SPM8. We found increased activity in prefrontal areas and decreased activity in the amygdala and hippocampal regions in conditions of lidocaine versus placebo. In addition, systemic lidocaine reduced activity in the primary sensory cortex, supplemental motor area, and putamen. Although lidocaine is a nonspecific sodium channel blocker and sodium channels are ubiquitous throughout the nervous system, these results indicate that lidocaine influences specific regions of the brain. The exact mechanism remains unclear, and further analysis and data are required to improve our understanding of the analgesic effects of lidocaine.
(254) Antinociceptive effect of recombinant neuroprogenitor intraspinal transplants in models of peripheral and central neuropathic pain S Jergova, M Varghese, D Collante, S Bartley, S Gajavelli, and J Sagen; University of Miami, Miami Project, Miami, FL Hypothesized mechanisms underlying chronic neuropathic pain following injury to the peripheral or central nervous system include increased hyperexcitability of spinal dorsal horn neurons due to loss or dysfunction of inhibitory g-aminobutyric acid (GABA)-ergic interneurons, and enhanced excitatory glutamate signaling through NMDA receptors. Restoration of inhibitory tone and/ or reduction of hyperexcitability via transplantation of selected cell types is a potential long-term intervention. The use of a recombinant neuronal progenitor cell (NPC) approach targeting GABA and glutamatergic signaling was evaluated in these experiments. Pre-differentiated rat GABAergic NPCs were intraspinally injected into rats with peripheral nerve injury-induced pain using sciatic nerve injury model. An improvement in behavioral outcome was observed for mechanical hyperalgesia and cold allodynia. Concurrent intrathecal injection of serine-histogranin (SHG), an NMDA antagonist, enhanced the analgesic effect of grafted cells. In accordance with behavioral data we found decreased number of c-Fos positive neurons in the superficial dorsal horn laminae in SHG treated rats, suggesting attenuated injury-induced excitation of nociceptive spinal neurons. For site-specific release of SHG a recombinant NPC capable of releasing GABA and SHG were engineered and intraspinally transplanted into rats after peripheral nerve injury. An markedly enhanced attenuation of cold allodynia and modestly attenuated mechanical hyperalgesia were observed. Intraspinal injection of GABAergic NPC was also used in the clip compression model of below-level pain after spinal cord injury. Beneficial effects in reducing tactile and cold allodynia were observed for several weeks post grafting. Our results suggest that transplantation of GABAergic NPC can attenuate peripheral and central nerve injury-induced chronic pain and that enhancement of this approach could be achieved by genetic modification of grafted cells. Supported by NS51667.
(253) How does physical activity relate to cognitive pain modulation in women?
(255) Morphine induces pain behavior and iGluR4 upregulation in murine spinal cord
M Shields, L Ellingson, A Stegner, and D Cook; University of Wisconsin-Madison, Madison, WI
A Baker, S Zhou, G Hargett, J Moron-Concepcion, and S Carlton; University of Texas Medical Branch, Galveston, TX
Fibromyalgia (FM) has been conceptualized as a disorder of the central nervous system (CNS), characterized by augmented sensory processing and an inability to effectively modulate pain. We previously reported that physical activity (PA) is related to brain processing of pain, providing preliminary evidence for a potential mechanism of pain management through exercise. The purpose of this study was to extend our previous work and examine whether PA was related to pain modulation. Thirty-six women (16 FM and 20 Control) completed self-report and accelerometer measures of PA and underwent functional magnetic resonance imaging of painful heat, administered alone and during a distracting cognitive task. For healthy controls, accelerometer data were significantly (p<0.005) and positively related to brain responses to pain during the cognitive task in regions often implicated in pain modulation (left anterior and posterior insula, right anterior insula, right dorsal and ventral lateral prefrontal and right orbital frontal cortices (r2=0.60). Significant (p<0.005) negative relationships occurred in left lateral prefrontal, left dorsolateral prefrontal and left middle frontal cortices (r2=0.61). Self-reported PA was positively related (p<0.05) to right orbital frontal cortex (r2=0.56) activity and changes in pain ratings due to the distracting cognitive task (r2=0.25). For FM patients, accelerometer data were negatively (p<0.005) related to activity in the left orbital frontal, and right and left inferior medial frontal cortices (r2=0.77). No significant relationships were found for self-reported PA and brain responses to pain during the cognitive task in FM patients and neither self-reported nor accelerometer measures were related to changes in pain ratings due to the distracting cognitive task. These preliminary results support a role for PA in pain modulation for healthy controls, but not FM patients. Experiments designed to increase PA levels may help further understand how exercise can be used to effectively treat FM. Supported by a grant from NIAM/NIH AR50969.
Studies highlight AMPA receptors (AMPAR) in morphine-induced dependence and withdrawal. Marked changes in AMPAR expression occur in the hippocampus of mice treated with morphine for two days every 12 hr. Using the same morphine injection paradigm, our study investigates morphine-induced pain behaviors and changes in AMPAR expression in the spinal cord. Mice received morphine (5, 8, 10, and 15 mg/kg, i.p.) or saline (n = 9-10/group) over 2 days, every 12 hr. Morphine-treated mice showed: a) mechanical allodynia at 12hr and 6 days post-morphine, b) cold allodynia (-5 C61 C) at 12 hr only and c) no heat hyperalgesia (46 C60.5 C). Immunostaining for AMPA iGluR4 in the spinal cord showed increases in lamina (L) III-V in morphine-treated mice 6 days post morphine treatment. The behavioral sensitization may reflect changes in expression/function of TRPM8 and/or TRPA1 receptors, which are implicated in cold-mechanical sensitivity. NK-1 receptor-expressing projection neurons in LIII-V are strongly labeled for iGluR41 and receive input from nociceptors. Upregulation of iGluR4 suggests enhanced synaptic input from nociceptors to these cells, and this could be one mechanism producing mechanical and cold sensitivity. Work was supported by NS027910 and DA027460. (Todd, EJN 2009)