Presynaptic Inhibition of Pain and Touch in the Spinal Cord: From Receptors to Circuits

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.

Neuropathic Pain: How to Assess and Treat a Maladaptive Pain Response

Neuropathic pain is associated with primary lesion or dysfunction of the peripheral and central nerve systems, affecting up to 10% of the general population. Although both nociceptive pain and neuropathic pain utilize the same nervous system pathways, physiologic differences exist in the pathologic mechanism, clinical presentation, and treatments. Ectopic activity in primary afferent fibers, excitatory and inhibitory somatosensory signaling, nociceptive neuron alterations, and central pain modulation have been implicated in neuropathic pain. These neuropathic mechanisms are associated with the complexity of symptoms, difficult treatment decisions, and challenging poor outcomes. Treatment options include pharmacologic (e.g., anticonvulsants, antidepressants, lidocaine, N-methyl-D-aspartate antagonist, opioids), physical, psychological (e.g., cognitive behavioral therapy), or interventional management (e.g., peripheral or neuro-axial nerve blockade, spinal cord stimulators, intrathecal medications). Medication selection should be individualized, considering patients’ symptoms and potential beneficial or deleterious effects (side effects) on comorbidities. The interventional management of chronic neuropathic pain should be considered for patients who have not responded to pharmacologic and non-interventional treatments, as an integral component of a more comprehensive approach. This article presents an overview of physiological mechanisms, clinical presentation, and assessment of neuropathic pain, and discusses treatment options for neuropathic pain.

Branching points of primary afferent fibers are vital for the modulation of fiber excitability by epidural DC polarization and by GABA in the rat spinal cord

Polarization of sensory fibers traversing dorsal columns of the spinal cord may considerably increase the excitability of these fibers. We show that this involves the effects of current at branching points of afferent fibers and depends on extrasynaptic of GABA. These results contribute to our understanding of the mechanism underlying plasticity of activation of nerve fibers and may be used to increase the effectiveness of epidural stimulation in humans and recovery of spinal functions.

Purinergic signaling as a basis of acupuncture-induced analgesia

This review summarizes experimental evidence indicating that purinergic mechanisms are causally involved in acupuncture (AP)-induced analgesia. Electroacupuncture (EAP) and manual AP release at pain-relevant acupoints ATP which may activate purinergic P2X receptors (Rs) especially of the P2X3 type situated at local sensory nerve endings (peripheral terminals of dorsal root ganglion [DRG] neurons); the central processes of these neurons are thought to inhibit via collaterals of ascending dorsal horn spinal cord neurons, pain-relevant pathways projecting to higher centers of the brain. In addition, during AP/EAP non-neuronal P2X4 and/or P2X7Rs localized at microglial cells of the CNS become activated at the spinal or supraspinal levels. In consequence, these microglia secrete bioactive compounds such as growth factors, cytokines, chemokines, reactive oxygen, and nitrogen species, which modulate the ascending neuronal pathways conducting painful stimuli. Alternatively, ATP released at acupoints by AP/EAP may be enzymatically degraded to adenosine, stimulating in loco presynaptic A1Rs exerting an inhibitory influence on the primary afferent fibers (the above mentioned pain-sensing peripheral terminals of DRG neurons) which thereby fail to conduct action potentials to the spinal cord dorsal horn. The net effect of the stimulation of P2X3, P2X4, P2X7, and A1Rs by the AP/EAP-induced release of ATP/adenosine at certain acupoints will be analgesia.