Abstract:Pain is a percept of critical importance to our daily survival. In most cases, it serves both an adaptive function by helping us respond appropriately in a potentially hostile environment and also a protective role by alerting us to tissue damage. Normally, it is evoked by the activation of peripheral nociceptive nerve endings and the subsequent relay of information to distinct cortical and sub-cortical regions, but under pathological conditions that result in chronic pain, it can become spontaneous. Given tha… Show more
“…1 ), we also suggest that activity of GABA- and glycinergic inhibitory receptor systems are necessary to support BDNF-induced Ca 2+ fluctuations. Given the role of GABA and glycine in sensory processing associated with chronic pain 33 , it is possible that BDNF-induced fluctuations are important for pathophysiology of neuropathic pain. Figure 6 Working model summarizing the effects of chronic BDNF on SDH neurons in this study.…”
Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain. However, the mechanisms of BDNF action on specific neuronal populations in the spinal superficial dorsal horn (SDH) requires further study. We used chronic BDNF treatment (200 ng/ml, 5–6 days) of defined-medium, serum-free spinal organotypic cultures to study intracellular calcium ([Ca2+]i) fluctuations. A detailed quantitative analysis of these fluctuations using the Frequency-independent biological signal identification (FIBSI) program revealed that BDNF simultaneously depressed activity in some SDH neurons while it unmasked a particular subpopulation of ‘silent’ neurons causing them to become spontaneously active. Blockade of gap junctions disinhibited a subpopulation of SDH neurons and reduced BDNF-induced synchrony in BDNF-treated cultures. BDNF reduced neuronal excitability assessed by measuring spontaneous excitatory postsynaptic currents. This was similar to the depressive effect of BDNF on the [Ca2+]i fluctuations. This study reveals novel regulatory mechanisms of SDH neuronal excitability in response to BDNF.
“…1 ), we also suggest that activity of GABA- and glycinergic inhibitory receptor systems are necessary to support BDNF-induced Ca 2+ fluctuations. Given the role of GABA and glycine in sensory processing associated with chronic pain 33 , it is possible that BDNF-induced fluctuations are important for pathophysiology of neuropathic pain. Figure 6 Working model summarizing the effects of chronic BDNF on SDH neurons in this study.…”
Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain. However, the mechanisms of BDNF action on specific neuronal populations in the spinal superficial dorsal horn (SDH) requires further study. We used chronic BDNF treatment (200 ng/ml, 5–6 days) of defined-medium, serum-free spinal organotypic cultures to study intracellular calcium ([Ca2+]i) fluctuations. A detailed quantitative analysis of these fluctuations using the Frequency-independent biological signal identification (FIBSI) program revealed that BDNF simultaneously depressed activity in some SDH neurons while it unmasked a particular subpopulation of ‘silent’ neurons causing them to become spontaneously active. Blockade of gap junctions disinhibited a subpopulation of SDH neurons and reduced BDNF-induced synchrony in BDNF-treated cultures. BDNF reduced neuronal excitability assessed by measuring spontaneous excitatory postsynaptic currents. This was similar to the depressive effect of BDNF on the [Ca2+]i fluctuations. This study reveals novel regulatory mechanisms of SDH neuronal excitability in response to BDNF.
“…A loss of inhibition mediated by GABA has been observed in both inflammatory and neuropathic pain: As evidenced in several animal models of chronic pain, both pre- and postsynaptic inhibitions become less efficient, leading the dorsal horn to a state of hyperexcitability [ 4 , 70 , 71 ].…”
Section: Modifications Of Presynaptic Inhibition In Chronic Painmentioning
confidence: 99%
“…The variety of neurons in the spinal cord makes the investigation of dorsal horn circuits difficult. Based on the expression of distinct neurochemical markers, several classes of neurons have been identified in rodent lamina I, II, and III of the dorsal horn, exhibiting different morphologies and functional properties [ 1 , 2 , 3 , 4 ]. The transgenic expression of fluorescent proteins, such as EGFP or tdTomato, driven by a cell-type-specific promoter, has allowed the characterization of morphological and electrophysiological properties of specific neuron populations.…”
Sensory primary afferent fibers, conveying touch, pain, itch, and proprioception, synapse onto spinal cord dorsal horn neurons. Primary afferent central terminals express a wide variety of receptors that modulate glutamate and peptide release. Regulation of the amount and timing of neurotransmitter release critically affects the integration of postsynaptic responses and the coding of sensory information. The role of GABA (γ-aminobutyric acid) receptors expressed on afferent central terminals is particularly important in sensory processing, both in physiological conditions and in sensitized states induced by chronic pain. During the last decade, techniques of opto- and chemogenetic stimulation and neuronal selective labeling have provided interesting insights on this topic. This review focused on the recent advances about the modulatory effects of presynaptic GABAergic receptors in spinal cord dorsal horn and the neural circuits involved in these mechanisms.
“…All of the inhibitory circuits discussed herein receive excitatory drive either directly or indirectly from the central terminals of primary afferent fibers. These circuits act to regulate the level of activity within last order output neurons through both direct and indirect mechanisms [ 12 , 13 , 14 ].…”
The ability to sense and move within an environment are complex functions necessary for the survival of nearly all species. The spinal cord is both the initial entry site for peripheral information and the final output site for motor response, placing spinal circuits as paramount in mediating sensory responses and coordinating movement. This is partly accomplished through the activation of complex spinal microcircuits that gate afferent signals to filter extraneous stimuli from various sensory modalities and determine which signals are transmitted to higher order structures in the CNS and to spinal motor pathways. A mechanistic understanding of how inhibitory interneurons are organized and employed within the spinal cord will provide potential access points for therapeutics targeting inhibitory deficits underlying various pathologies including sensory and movement disorders. Recent studies using transgenic manipulations, neurochemical profiling, and single-cell transcriptomics have identified distinct populations of inhibitory interneurons which express an array of genetic and/or neurochemical markers that constitute functional microcircuits. In this review, we provide an overview of identified neural components that make up inhibitory microcircuits within the dorsal and ventral spinal cord and highlight the importance of inhibitory control of sensorimotor pathways at the spinal level.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
