Spinal Allografts of Adrenal Medulla Block Nociceptive Facilitation in the Dorsal Horn

Transplantation of chromaffin cells into the lumbar subarachnoid space has been found to produce analgesia, most conspicuously against chronic neuropathic pain. To ascertain the neurophysiological mechanism, we recorded electrical activity from wide-dynamic-range dorsal horn neurons in vivo, measuring the short-lasting homosynaptic facilitatory effect known as windup, which is induced by repetitive C-fiber input. Rats were given adrenal medulla allografts, or, as controls, striated-muscle allografts. The adrenal-transplanted rats showed analgesia 3–4 wk after transplantation, measured as a reduction in flinching reflexes 30–55 min after subcutaneous formalin injection. Recordings were made under halothane anesthesia, 3–7 days following the behavioral testing. The average C-fiber response and subsequent afterdischarge were facilitated severalfold in control rats by 1-Hz cutaneous electrical stimulation. Such facilitation was essentially absent in adrenal-transplanted animals and also in the A-fiber response of both preparations. Extirpation of transplanted tissue several hours prior to recording did not significantly affect this difference. In conclusion, the adrenal transplants block short-term spinal nociceptive facilitation, probably by stimulating some persistent cellular process that may be an important determinant, but not the only one, of their analgesic effect.

Download Full-text

Selective Cannabinoid CB1 Receptor Activation Inhibits Spinal Nociceptive Transmission In Vivo

Journal of Neurophysiology ◽

10.1152/jn.2001.86.6.3061 ◽

2001 ◽

Vol 86 (6) ◽

pp. 3061-3064 ◽

Cited By ~ 62

Author(s):

Sara Kelly ◽

Victoria Chapman

Keyword(s):

Dorsal Horn ◽

Receptor Activation ◽

Evoked Responses ◽

Somatosensory Processing ◽

Sprague Dawley ◽

Nociceptive Transmission ◽

Dorsal Horn Neurons ◽

Anesthetized Rats ◽

C Fiber

Cannabinoid1 (CB1) receptors are located at CNS sites, including the spinal cord, involved in somatosensory processing. Analgesia is one of the tetrad of behaviors associated with cannabinoid agonists. Here, effects of a potent cannabinoid CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA) on evoked responses of dorsal horn neurons in anesthetized rats were investigated. Extracellular recordings of convergent dorsal horn neurons were made in halothane anesthetized Sprague-Dawley rats ( n = 16). Effects of spinal application of ACEA on electrically evoked responses of dorsal horn neurons were studied. Mean maximal effects of 0.5, 5, 50, and 500 ng/50 μl ACEA on the C-fiber-mediated postdischarge response were 79 ± 6, 62 ± 10, and 54 ± 7% ( P < 0.01), 45 ± 6% ( P < 0.01), of control, respectively. ACEA (500 ng/50 μl) also reduced the C-fiber-evoked nonpotentiated responses of neurons (59 ± 9% of control, P < 0.05) and Aδ-fiber-evoked responses of neurons (68 ± 10% of control, P < 0.01). Minor effects of ACEA on Aβ-fiber-evoked responses were observed. Spinal pre-administration of the selective CB1 receptor antagonist SR141716A (0.01 μg/50 μl) significantly reduced effects of ACEA (500 ng/50 μl) on postdischarge responses of dorsal horn neurons. This study demonstrates that spinal CB1 receptors modulate the transmission of C- and Aδ-fiber-evoked responses in anesthetized rats; this may reflect pre- and/or postsynaptic effects of cannabinoids on nociceptive transmission. CB1 receptors inhibit synaptic release of glutamate in rat dorsolateral striatum, a similar mechanism of action may underlie the effects of ACEA on noxious evoked responses of spinal neurons reported here.

Download Full-text

Application of Nucleus Pulposus to L5 Dorsal Root Ganglion in Rats Enhances Nociceptive Dorsal Horn Neuronal Windup

Journal of Neurophysiology ◽

10.1152/jn.00762.2004 ◽

2005 ◽

Vol 94 (1) ◽

pp. 35-48 ◽

Cited By ~ 23

Author(s):

J. M. Cuellar ◽

P. X. Montesano ◽

J. F. Antognini ◽

E. Carstens

Keyword(s):

Dorsal Root Ganglion ◽

Dorsal Horn ◽

Nucleus Pulposus ◽

Central Sensitization ◽

Dorsal Root ◽

Dynamic Range ◽

Spinal Neuron ◽

Peripheral Sensitization ◽

Dorsal Horn Neurons ◽

C Fiber

Herniation of the nucleus pulposus (NP) from lumbar intervertebral discs commonly results in radiculopathic pain possibly through a neuroinflammatory response. NP sensitizes dorsal horn neuronal responses, but it is unknown whether this reflects a central or peripheral sensitization. To study central sensitization, we tested if NP enhances windup—the progressive increase in the response of a nociceptive spinal neuron to repeated electrical C-fiber stimulation—a phenomenon that may partly account for temporal summation of pain. Single-unit recordings were made from wide dynamic range (WDR; n = 36) or nociceptive-specific (NS; n = 8) L5 dorsal horn neurons in 44 isoflurane-anesthetized rats. Subcutaneous electrodes delivered electrical stimuli (20 pulses, 3 times the C-fiber threshold, 0.5 ms) to the receptive field on the hindpaw. Autologous NP was harvested from a tail disc and placed onto the L5 dorsal root ganglion after recording of baseline responses ( n = 22). Controls had saline applied similarly ( n = 22). Electrical stimulus trains (0.1, 0.3, and 1 Hz; 5-min interstimulus interval) were repeated every 30 min for 3–6 h after each treatment. The total number of evoked spikes (summed across all 20 stimuli) to 0.1 Hz was enhanced 3 h after NP, mainly in the after-discharge (AD) period (latency > 400 ms). Total responses to 0.3 and 1.0 Hz were also enhanced at ≥60 min after NP in both the C-fiber (100- to 400-ms latency) and AD periods, whereas the absolute windup (C-fiber + AD − 20 times the initial response) increased at ≥90 min after treatment. In saline controls, windup was not enhanced at any time after treatment for any stimulus frequency, although there was a trend toward enhancement at 0.3 Hz. These results are consistent with NP-induced central sensitization. Mechanical responses were not significantly enhanced after saline or NP treatment. We speculate that inflammatory agents released from (or recruited by) NP affect the dorsal root ganglion (and/or are transported to cord) to enhance primary afferent excitation of nociceptive dorsal horn neurons.

Download Full-text

306 IN VIVO IMAGING OF Ca 2+ GRADIENTS IN SPINAL DORSAL HORN NEURONS

European Journal of Pain ◽

10.1016/s1090-3801(09)60309-8 ◽

2009 ◽

Vol 13 (S1) ◽

Author(s):

M. Gassner ◽

M. Wagner ◽

H. Fischer ◽

R. Drdla ◽

T. Jäger ◽

...

Keyword(s):

Dorsal Horn ◽

In Vivo Imaging ◽

Spinal Dorsal Horn ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Spinal Dorsal Horn Neurons

Download Full-text

Spinal substance P release in vivo during the induction of long-term potentiation in dorsal horn neurons

Pain ◽

10.1016/s0304-3959(01)00414-6 ◽

2002 ◽

Vol 96 (1) ◽

pp. 49-55 ◽

Cited By ~ 39

Author(s):

Abdullahi Warsame Afrah ◽

Atle Fiskå ◽

Johannes Gjerstad ◽

Henrik Gustafsson ◽

Arne Tjølsen ◽

...

Keyword(s):

Substance P ◽

Dorsal Horn ◽

Long Term Potentiation ◽

Dorsal Horn Neurons ◽

P Release ◽

Term Potentiation ◽

Substance P Release

Download Full-text

Developmental Changes in the Fidelity and Short-Term Plasticity of GABAergic Synapses in the Neonatal Rat Dorsal Horn

Journal of Neurophysiology ◽

10.1152/jn.01342.2007 ◽

2008 ◽

Vol 99 (6) ◽

pp. 3144-3150 ◽

Cited By ~ 18

Author(s):

Rachel A. Ingram ◽

Maria Fitzgerald ◽

Mark L. Baccei

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Receptive Fields ◽

Neuronal Firing ◽

Neonatal Rat ◽

Superficial Dorsal Horn ◽

Short Term ◽

Dorsal Horn Neurons ◽

Gabaergic Synapses

The lower thresholds and increased excitability of dorsal horn neurons in the neonatal rat suggest that inhibitory processing is less efficient in the immature spinal cord. This is unlikely to be explained by an absence of functional GABAergic inhibition because antagonism of γ-aminobutyric acid (GABA) type A receptors augments neuronal firing in vivo from the first days of life. However, it is possible that more subtle deficits in GABAergic signaling exist in the neonate, such as decreased reliability of transmission or greater depression during repetitive stimulation, both of which could influence the relative excitability of the immature spinal cord. To address this issue we examined monosynaptic GABAergic inputs onto superficial dorsal horn neurons using whole cell patch-clamp recordings made in spinal cord slices at a range of postnatal ages (P3, P10, and P21). The amplitudes of evoked inhibitory postsynaptic currents (IPSCs) were significantly lower and showed greater variability in younger animals, suggesting a lower fidelity of GABAergic signaling at early postnatal ages. Paired-pulse ratios were similar throughout the postnatal period, whereas trains of stimuli (1, 5, 10, and 20 Hz) revealed frequency-dependent short-term depression (STD) of IPSCs at all ages. Although the magnitude of STD did not differ between ages, the recovery from depression was significantly slower at immature GABAergic synapses. These properties may affect the integration of synaptic inputs within developing superficial dorsal horn neurons and thus contribute to their larger receptive fields and enhanced afterdischarge.

Download Full-text

Role of substance P in the modulation of C-fiber-evoked responses of spinal dorsal horn neurons

Brain Research ◽

10.1016/0006-8993(95)01384-9 ◽

1996 ◽

Vol 710 (1-2) ◽

pp. 197-203 ◽

Cited By ~ 31

Author(s):

Dénes Budai ◽

Alice A. Larson

Keyword(s):

Substance P ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Evoked Responses ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

C Fiber ◽

Spinal Dorsal Horn Neurons

Download Full-text

Electrophysiological Changes in Adult Rat Dorsal Horn Neurons After Neonatal Peripheral Inflammation

Journal of Neurophysiology ◽

10.1152/jn.01019.2002 ◽

2003 ◽

Vol 90 (1) ◽

pp. 73-80 ◽

Cited By ~ 32

Author(s):

Yuan Bo Peng ◽

Qing Dong Ling ◽

M. A. Ruda ◽

Daniel R. Kenshalo

Keyword(s):

Spinal Cord ◽

Receptive Field ◽

Dorsal Horn ◽

Dynamic Range ◽

High Threshold ◽

Peripheral Inflammation ◽

Mechanical Stimuli ◽

Neonatal Rats ◽

Adult Rats ◽

Dorsal Horn Neurons

Neonatal peripheral inflammation has been shown to produce profound anatomical changes in the dorsal horn of adult rats. In this study, we explored whether parallel physiological changes exist. Neonatal rats were injected with complete Freund's adjuvant (CFA) into the left hind paw. At 8–10 wk of age, single dorsal horn neurons were recorded in response to graded intensities of mechanical stimuli delivered to the receptive field. In addition, cord dorsum potentials, produced by electrical stimuli delivered to the left sciatic nerve at 2.5× threshold, were recorded bilaterally from L2 to S3. There were significant increases in background activity and responses to brush and pinch in neonatal rats that were treated with CFA, as compared with control rats. Further analysis showed similar significant changes when dorsal horn neurons were categorized into wide dynamic range (WDR), high-threshold (HT), and low-threshold (LT) groups. The receptive field was significantly larger in neonatally treated rats as compared with control rats. Additionally, there was a significant increase in the response to a 49°C heat stimulus in neonatally treated rats as compared with control rats. There was also a trend for the amplitudes of N1, N2, and P waves of the cord dorsum potential to increase and latencies to decrease in neonatally treated rats, but no significant differences were detected between different levels of the spinal cord (L2 to S3). These data further support the notion that anatomical and physiological plasticity changes occurred in the spinal cord following early neonatal CFA treatment.

Download Full-text

Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons

Molecular Brain ◽

10.1186/s13041-020-00669-3 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Guangchen Ji ◽

Volker Neugebauer

Keyword(s):

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Facilitatory Effect ◽

Functional Coupling ◽

Kappa Opioid ◽

Positive Direction ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Nociceptive Processing ◽

Spinal Dorsal Horn Neurons

Abstract The amygdala plays an important role in the emotional-affective aspects of behaviors and pain, but can also modulate sensory aspect of pain (“nociception”), likely through coupling to descending modulatory systems. Here we explored the functional coupling of the amygdala to spinal nociception. We found that pharmacological activation of neurons in the central nucleus of the amygdala (CeA) increased the activity of spinal dorsal horn neurons; and this effect was blocked by optogenetic silencing of corticotropin releasing factor (CRF) positive CeA neurons. A kappa opioid receptor (KOR) agonist (U-69,593) was administered into the CeA by microdialysis. KOR was targeted because of their role in averse-affective behaviors through actions in limbic brain regions. Extracellular single-unit recordings were made of CeA neurons or spinal dorsal horn neurons in anesthetized transgenic Crh-Cre rats. Neurons responded more strongly to noxious than innocuous stimuli. U-69,593 increased the responses of CeA and spinal neurons to innocuous and noxious mechanical stimulation of peripheral tissues. The facilitatory effect of the agonist was blocked by optical silencing of CRF-CeA neurons though light activation of halorhodopsin expressed in these neurons by viral-vector. The CRF system in the amygdala has been implicated in aversiveness and pain modulation. The results suggest that the amygdala can modulate spinal nociceptive processing in a positive direction through CRF-CeA neurons and that KOR activation in the amygdala (CeA) has pro-nociceptive effects.

Download Full-text