The Increased In Vivo Firing of Pyramidal Cells But not Interneurons in the Anterior Cingulate Cortex After Neuropathic Pain

Chronic pain damages the balance between excitation and inhibition in the sensory cortex. It has been confirmed that the activity of cortical glutamatergic pyramidal cells increases after chronic pain. However, whether the activity of inhibitory interneurons synchronized changed remains obscure, especially in in vivo conditions. In the present study, we checked the firing rate of pyramidal cells and interneurons in the anterior cingulate cortex, a main cortical area for the regulation of nociceptive information in mice with spared nerve injury by using in vivo multi-channel recording system. We found that the firing rate of pyramidal cells but not interneurons increased in the ACC, which is further confirmed by the increased FOS expression in pyramidal cells but not interneurons, in mice with neuropathic pain. Selectively high frequency stimulation of the ACC nociceptive afferent fibers only potentiated the activity of pyramidal cells either. Our results thus suggest that the increased activity of pyramidal cells contributes to the damaged E/I balance in the ACC and is important for the pain hypersensitivity in mice with neuropathic pain.

The parabrachial-to-amygdala pathway provides aversive information to induce avoidance behavior in mice

The neuronal circuitry for pain signals has been intensively studied for decades. The external lateral parabrachial nucleus (PB) was shown to play a crucial role in nociceptive information processing. Previous work, including ours, has demonstrated that stimulating the neuronal pathway from the PB to the central region of the amygdala (CeA) can substitute for an actual pain signal to drive an associative form of threat/fear memory formation. However, it is still unknown whether activation of the PB–CeA pathway can directly drive avoidance behavior, escape behavior, or only acts as strategic freezing behavior for later memory retrieval. To directly address this issue, we have developed a real-time Y-maze conditioning behavioral paradigm to examine avoidance behavior induced by optogenetic stimulation of the PB–CeA pathway. In this current study, we have demonstrated that the PB–CeA pathway carries aversive information that can directly trigger avoidance behavior and thereby serve as an alarm signal to induce adaptive behaviors for later decision-making.

Orexinergic descending inhibitory pathway mediates linalool odor-induced analgesia in mice

Linalool odor exposure induces an analgesic effect in mice. This effect disappeared in the anosmic model mice, indicating that olfactory input evoked by linalool odor triggered this effect. Furthermore, hypothalamic orexinergic neurons play a pivotal role in this effect. However, the neuronal circuit mechanisms underlying this effect have not been fully addressed. In this study, we focused on the descending orexinergic projection to the spinal cord and examined whether this pathway contributes to the effect. We assessed the effect of intrathecal administration of orexin receptor antagonists on linalool odor-induced analgesia in the tail capsaicin test. We found that the selective orexin type 1 receptor antagonist, but not the selective orexin type 2 receptor antagonist, prevented the odor-induced analgesic effect. Furthermore, immunohistochemical analyses of c-Fos expression induced by the capsaicin test revealed that neuronal activity of spinal cord neurons was suppressed by linalool odor exposure, which was prevented by intrathecal administration of the orexin 1 receptor antagonist. These results indicate that linalool odor exposure drives the orexinergic descending pathway and suppresses nociceptive information flow at the spinal level.

Distinct nociresponsive region in mouse primary somatosensory cortex

Nociception, somatic discriminative aspects of pain, is represented in the primary somatosensory cortex (S1), as is touch, but the separation and the interaction of the two modalities within S1 remain unclear. Here, we show the spatially-distinct tactile and nociceptive processing in the granular barrel field (BF) and the adjacent dysgranular region (Dys) in mouse S1. Simultaneous recording of the multiunit activity across subregions reveals that Dys responses are selective to noxious input whereas those of BF are to tactile input. At the single neuron level, nociceptive information is represented separately from the tactile information in Dys layer 2/3. In contrast, both modalities are converged in a layer 5 neuron in each region. Interestingly, the two modalities interfere with each other in both regions. We further demonstrate that Dys, but not BF, activity is critically involved in neuropathic pain and pain behavior, and thus provide evidence that Dys is a center specialized for nociception in S1.

Cervical Cordotomy in Terminal Cancer: Pain Relieving in Oncological Treatment

Cordotomy consists in the discontinuation of the lateral spinothalamic tract (LST) in the anterolateral quadrant of the spinal cord, which aims to reduce the transference of nociceptive information in the dorsal horn of the gray matter of the spinal cord to the somatosensory cortex. The main indication is for patients with terminal cancer that have a low life expectancy. It improves the quality of life by relieving pain. The results are promising and the pain relief rate varies between 69 and 100%. Generally speaking, the complications are mostly temporary and not remarkable.

Inhibition of Fast Nerve Conduction Produced by Analgesics and Analgesic Adjuvants—Possible Involvement in Pain Alleviation

Nociceptive information is transmitted from the periphery to the cerebral cortex mainly by action potential (AP) conduction in nerve fibers and chemical transmission at synapses. Although this nociceptive transmission is largely inhibited at synapses by analgesics and their adjuvants, it is possible that the antinociceptive drugs inhibit nerve AP conduction, contributing to their antinociceptive effects. Many of the drugs are reported to inhibit the nerve conduction of AP and voltage-gated Na+ and K+ channels involved in its production. Compound action potential (CAP) is a useful measure to know whether drugs act on nerve AP conduction. Clinically-used analgesics and analgesic adjuvants (opioids, non-steroidal anti-inflammatory drugs, α2-adrenoceptor agonists, antiepileptics, antidepressants and local anesthetics) were found to inhibit fast-conducting CAPs recorded from the frog sciatic nerve by using the air-gap method. Similar actions were produced by antinociceptive plant-derived chemicals. Their inhibitory actions depended on the concentrations and chemical structures of the drugs. This review article will mention the inhibitory actions of the antinociceptive compounds on CAPs in frog and mammalian peripheral (particularly, sciatic) nerves and on voltage-gated Na+ and K+ channels involved in AP production. Nerve AP conduction inhibition produced by analgesics and analgesic adjuvants is suggested to contribute to at least a part of their antinociceptive effects.

Сentral and peripheral mechanisms of mu-opioid analgesia and tolerance

Objective – An analysis of the basic science and clinical publications found in PubMed, Medline, and Web of Science. The search covered modern laboratory and clinical mechanisms of peripheral mu opioid analgesia, the role of peripheral mu receptors in systemic analgesia and the development of tolerance to the analgesic effect of opioids. The review discusses the regulatory mechanisms of synthesis and transport of mu-opioid receptors in the primary afferent neurons and the molecular mechanisms responsible for modulating the conduction of nociceptive information from the periphery to the spinal cord. According to some authors, the peripheral component can account for 50-90% of the total analgesic effect after the systemic administration of morphine and methadone. The review reports on the important role of glycoprotein-P and the blood-brain barrier transport system in modulating the peripheral component of the analgesic effect of morphine as well as the synergistic interaction between central and peripheral mu receptors. The results of the reviewed studies convincingly show the key role of peripheral mu receptors in the development of tolerance to the analgesic effect of morphine after its systemic administration. The mechanisms of opioid tolerance also involve peripheral anti-opioid, pronociceptive systems such as NMDA receptors. It is well known that the same mechanisms are involved in maintaining peripheral hyperalgesia and allodynia. The development of analgesic drugs that act on peripheral antinociceptive systems offers a promising perspective on the possible treatment of acute and chronic pain.

NEUROMODULATOR LIGAND-RECEPTOR SYSTEM TIP39 - PTH2R

Widely spread axon terminals of TIP39 neurons have a distribution similar to PTH2R containing neurons and their fibers which provides an anatomic base of neuromodulation action of TIP39. This functional and anatomic link- ing lets state that TIP39 and PTH2R form a neuromodulator ligand-receptor system. Basing on mechanisms of signal transmission used by TIP39 and PTH2R, they can form a neuromodulator system in many brain parts. TIP39-PTH2R system is a unique neuropeptide-receptor system, which localization and functions in the central nervous system differ from any other neuropeptides. Neuromodulator system TIP39-PTH2R predominantly participates in neuroendocrinal modulation by affecting the endocrinal system by means of its presence in several areas of hypothalamus. TIP39 influences neurons that contain somatostatin and corticotropin-releasing hormone. TIP39 can affect the release of adrenocorticotropin, luteinizing hormone, growth hormone and arginine-vasopressin from hypophysis. Experimental data prove that TIP39 modulates regulatory network of anxiety and depression, several aspects of stress reaction and also controls body temperature, participates in processing of auditory and nociceptive information. Physiological role of TIP39-PTH2R system is still to some extent unknown. However, distribution of PTH2R and TIP39 in tissues outside central nervous system assumes other potential physiological effects for this signal way. It is assumed that TIP39- PTH2R system should be probably considered as a potential therapeutic target for treatment of anxiety, depression and chronic pain, control and correction of neuroendocrine disruptions.

Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn

Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target.

Specialized cutaneous Schwann cells initiate pain sensation

An essential prerequisite for the survival of an organism is the ability to detect and respond to aversive stimuli. Current belief is that noxious stimuli directly activate nociceptive sensory nerve endings in the skin. We discovered a specialized cutaneous glial cell type with extensive processes forming a mesh-like network in the subepidermal border of the skin that conveys noxious thermal and mechanical sensitivity. We demonstrate a direct excitatory functional connection to sensory neurons and provide evidence of a previously unknown organ that has an essential physiological role in sensing noxious stimuli. Thus, these glial cells, which are intimately associated with unmyelinated nociceptive nerves, are inherently mechanosensitive and transmit nociceptive information to the nerve.