Terminals Of Primary Nociceptive Neurons Research Articles

The Input-Output Relation of Primary Nociceptive Neurons is Determined by the Morphology of the Peripheral Nociceptive Terminals.

The output from the peripheral terminals of primary nociceptive neurons, which detect and encode the information regarding noxious stimuli, is crucial in determining pain sensation. The nociceptive terminal endings are morphologically complex structures assembled from multiple branches of different geometry, which converge in a variety of forms to create the terminal tree. The output of a single terminal is defined by the properties of the transducer channels producing the generation potentials and voltage-gated channels, translating the generation potentials into action potential (AP) firing. However, in the majority of cases, noxious stimuli activate multiple terminals; thus, the output of the nociceptive neuron is defined by the integration and computation of the inputs of the individual terminals. Here, we used a computational model of nociceptive terminal tree to study how the architecture of the terminal tree affects the input-output relation of the primary nociceptive neurons. We show that the input-output properties of the nociceptive neurons depend on the length, the axial resistance (Ra), and location of individual terminals. Moreover, we show that activation of multiple terminals by a capsaicin-like current allows summation of the responses from individual terminals, thus leading to increased nociceptive output. Stimulation of the terminals in simulated models of inflammatory or neuropathic hyperexcitability led to a change in the temporal pattern of AP firing, emphasizing the role of temporal code in conveying key information about changes in nociceptive output in pathologic conditions, leading to pain hypersensitivity.SIGNIFICANCE STATEMENT Noxious stimuli are detected by terminal endings of primary nociceptive neurons, which are organized into morphologically complex terminal trees. The information from multiple terminals is integrated along the terminal tree, computing the neuronal output, which propagates toward the CNS, thus shaping the pain sensation. Here, we revealed that the structure of the nociceptive terminal tree determines the output of nociceptive neurons. We show that the integration of noxious information depends on the morphology of the terminal trees and how this integration and, consequently, the neuronal output change under pathologic conditions. Our findings help to predict how nociceptive neurons encode noxious stimuli and how this encoding changes in pathologic conditions, leading to pain.

A role for the purinergic receptor P2X3 in astrocytes in the mechanism of craniofacial neuropathic pain

The purinergic receptor P2X3, expressed in the central terminals of primary nociceptive neurons in the brainstem, plays an important role in pathological pain. However, little is known about expression of P2X3 in the brainstem astrocytes and its involvement in craniofacial pathologic pain. To address this issue, we investigated the expression of P2X3 in astrocytes in the trigeminal caudal nucleus (Vc) in a rat model of craniofacial neuropathic pain, chronic constriction injury of infraorbital nerve (CCI-ION). We found that 1) P2X3-immunoreactivity is observed in the brainstem astrocytes, preferentially in their fine processes, 2) the number of P2X3-positive fine astrocytic processes and the density of P2X3 in these processes were increased significantly in CCI-ION rats, compared to control rats, and 3) administration of MPEP, a specific mGluR5 antagonist, alleviated the mechanical allodynia and abolished the increase in density of P2X3 in fine astrocytic processes caused by CCI-ION. These findings reveal preferential expression of P2X3 in the fine astrocytic processes in the brainstem, propose a novel role of P2X3 in the fine astrocytic process in the mechanism of craniofacial neuropathic pain, and suggest that the expression of astrocytic P2X3 may be regulated by astrocytic mGluR5.

Central Terminal Sensitization of TRPV1 by Descending Serotonergic Facilitation Modulates Chronic Pain

The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediated by membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal horn to chronic pain has not been investigated directly. Combining primary sensory neuron-specific GCaMP3 imaging with a trigeminal neuropathic pain model, we detected robust neuronal hyperactivity in injured and uninjured nerves in the skin, soma in trigeminal ganglion, and central terminals in the spinal trigeminal nucleus. Extensive TRPV1 hyperactivity was observed in central terminals innervating all dorsal horn laminae. The central terminal TRPV1 sensitization was maintained by descending serotonergic (5-HT) input from the brainstem. Central blockade of TRPV1 or 5-HT/5-HT3A receptors attenuated central terminal sensitization, excitatory primary afferent inputs, and mechanical hyperalgesia in the territories of injured and uninjured nerves. Our results reveal central mechanisms facilitating central terminal sensitization underlying chronic pain.

Iontophoretically applied microtubule inhibitors induce transganglionic degenerative atrophy of primary central nociceptive terminals and abolish chronic autochtonous pain.

Transcutaneous iontophoresis of microtubule inhibitors (Vinblastin, Vincristin, Formyl-Leurosin) in rats induces depletion of fluoride-resistant acid phosphatase (FRAP) and transganglionic degenerative atrophy (trggl. deg. atr.) of the central terminals of primary nociceptive neurons, probably via blockade of axoplasmic transport in the peripheral sensory nerves. Radiochemical experiments prove that about 0.2% of the microtubule inhibitors applied iontophoretically at the skin reach the level of nociceptive axon terminals. 40 out of 48 patients suffering from chronic intractable pain of diverse etiology (postherpetic, paresthetic, ischaemic and trigeminal neuralgia, alcoholic and diabetic polyneuropathy, meralgia, brachialgia, discopathia, arthropathia and terminal pain) were successfully treated with Vinblastin or Vincristin iontophoresis. Iontophoretically applied microtubule inhibitors do not affect the blood cell count, have no side-effects and do not impair the skin at the site of application.

Molecular plasticity of primary nociceptive neurons: relations of the NGF- c-jun system to neurotomy and chronic pain

Neurotomy is widely used as a model of chronic, intractable pain, the proverbial "crux medicorum". Immunohistochemical aspects of this chronic pain model are discussed in this paper, with the aim of shedding new light on the pathomechanism and possible therapeutical consequences. Central terminals of nociceptive neurons contain substance P, somatostatin and calcitonin generelated peptide or exhibit fluoride resistant acid phosphatase and thiamine monophosphatase enzyme reaction in the superficial dorsal horn of the spinal cord and in analogous structures of the brain stem. These neuropeptides and neuroproteins are expressed by the related dorsal root ganglion cells and transported via orthograde axoplasmic transport via dorsal roots to the central nervous system. Transection of the ipsilateral, segmentally related peripheral sensory nerve results in transganglionic degenerative atrophy of central terminals of primary nociceptive neurons. Transganglionic degenerative atrophy is characterized by marked ultrastructural alterations superficially similar to, but essentially differing from the signs of Wallerian degeneration which ensue after dorsal rhizotomy. Transganglionic degenerative atrophy is accompanied by depletion of marker neuropeptides and enzymes, and later by the expression of vicarious neuropeptides such as vasoactive intestinal polypeptide, neuropeptide Y and galanin and of the enzyme choline acetyl transferase. Consequences of blockade of retrograde axoplasmic transport of the nerve growth factor elicited either by perineural application of microtubule inhibitors or by perineural administration of anti-nerve growth factor are similar to peripheral neurotomy. According to recent studies described in this paper, the blockade of nerve growth factor supply to primary nociceptive neurons induces activation of c-jun in nuclei of primary nociceptive neurons probably responsible for the plasticity of the neuropeptide and neuroprotein synthesizing machinery. In contrast, invasion of and formation of pericellular baskets by noradrenergic axons can be elicited only by axotomy and not by blockade of retrograde axoplasmic transport. Involvement of nerve growth factor and the nerve growth factor-dependent immediate early genes in neuroplasticity of neuropeptidergic primary sensory neurons raise the possibility of a gene therapy of chronic intractable pain.

Reversibility of microtubule inhibitor-induced transganglionic degenerative atrophy of central terminals of primary nociceptive neurons : Neuroscience, 7 (1982) 1149–1154

Reversibility of microtubule inhibitor-induced transganglionic degenerative atrophy of central terminals of primary nociceptive neurons : Neuroscience, 7 (1982) 1149–1154

Reversibility of microtubule inhibitor-induced transganglionic degenerative atrophy of central terminals of primary nociceptive neurons

Microtubule inhibitor Vinca alkaloids applied around a peripheral nerve induce transganglionic degenerative atrophy of the central terminals of primary nociceptive neurons. This effect is reversible: 40–50 days later the original histochemical structure of the central terminals is restored. Restoration of fluoride-resistant acid phosphatase activity (the marker enzyme of primary nociceptive neurons) in the Rolando substance is due to regenerative sprouting of the formerly atrophied central terminals. Since peripherally-applied Vinca alkaloids induce transganglionic degenerative atrophy of the central terminals without inducing Wallerian degeneration of the peripheral nerve, and since this effect (virtually a synaptic discoupling) is only temporary, this approach may be used in the treatment of otherwise intractable neuralgias without inducing irreparable alterations.

Regenerative synaptoneogenesis in the Mammalian spinal cord: dynamics of synaptochemical restoration in the Rolando Substance after transganglionic degenerative atrophy.

Crush injury of the sciatic nerve, that results in Wallerian degeneration of axons in the peripheral stump, induces, within 10-14 days, transganglionic degenerative atrophy of central terminals of primary nociceptive neurons in the ipsilateral substantia gelatinosa Rolandi of the segmentally related region of the spinal cord. Transganglionic degenerative atrophy is characterized by disappearance of fluoride-resistant acid phosphatase (FRAP) from the Rolando substance, normally exerted by primary nociceptive terminals. From the 40th postoperative day on, FRAP reaction starts to reappear in the formerly depleted Rolando substance. Restoration of FRAP reactivity reflects regenerative sprouting of formerly atrophied primary nociceptive terminals. Growth cones of primary nociceptive axons establish synapses with dendritic growth cones of substantia gelatinosal gelatinosal cells. Synaptoneogenesis in the Rolando substance follows medio-lateral and caudo-rostral gradients.