Nociceptive Messages Research Articles

Are Descending Control Pathways of the Lower Urinary Tract and Pain Overlapping Systems?

The functions of the lower urinary tract (LUT) are dependent upon neural circuits located in the brain, spinal cord and peripheral ganglia, organized as on-off switching circuits to regulate storage and periodic elimination of urine. Damage or disease in any of the nervous pathways controlling the lower urinary tract can cause impairment of normal bladder function. Nociceptive information from different organs are delivered to the dorsal horn of the spinal cord where a network of descending pathways projecting from cerebral structures either suppress or potentiate the passage of the nociceptive messages to the brain. Some of the central structures involved in the micturition reflexes and pain modulation are common, e.g. nucleus raphe magnum, nucleus locus coeruleus alpha, periacqueductal grey, etc. Functionally, however, their effects may be similar or contrasting. The central micturition reflexes and descending control pathways of pain also utilize common transmitters and transmitter systems with similar or different effects on micturition and pain, suggesting a certain degree of overlapping between these systems. All these findings have provided a rich palette of novel mechanisms potentially available for the improved control of LUT and pain. The proliferation of potential analgesic drug targets for the therapeutic manipulation of descending control of pain is testimony of a more (in comparison with LUT) intensive research programme in this field. Nevertheless, with the exception of parenteral administration of micro-opioids and spinal application of alpha(2)-AR agonists, no other approach has been extensively validated in the clinic. Great effort should be invested in the characterization of central mechanisms controlling the micturition reflexes, although the possibility to find novel drugs for micturition disorders with central effect appears to be problematic.

Plasticity of synaptic inhibition in mouse spinal cord lamina II neurons during early postnatal development and after inactivation of the glycine receptor α3 subunit gene

Synaptic inhibition mediated by GABA(A) receptors and glycine receptors (GlyRs) in the outer laminae of the spinal cord dorsal horn efficiently filters ascending nociceptive messages, controlling pathological pain symptoms. However, although many studies have utilized transgenic models to study spinal nociceptive processing, very little is known about the development of functional inhibitory synapses onto these interneurons in mice. Here we report that most interneurons in lamina II are placed under phasic control by both GABAergic and glycinergic synapses, a number of which exhibit dual GABA/glycine co-release. A developmental switch is also apparent: a subpopulation of lamina II interneurons controlled exclusively by either GABAergic or glycinergic synapses becomes detectable only after postnatal days 15 and 21, respectively. Using mice older than postnatal day 21, we also characterized the plastic changes in glycinergic transmission resulting from the inactivation of the GlyR alpha3 subunit gene, a key player in inflammatory pain pathways. This allowed us to demonstrate that synapses containing GlyR alpha3 contribute in large part to synaptic inhibition in lamina II. In Glra3 knockout mice, we found that synaptic currents at the remaining glycinergic synapses, containing GlyR alpha1, showed faster decay kinetics with unchanged amplitudes but increased frequency. These findings explain the absence of any basal nociceptive hypersensitivity in Glra3 knockout mice, as GlyR alpha1 is still available for mediating synaptic inhibition at lamina II synapses, but cannot be modulated by the prostaglandin-E-prostanoid type 2 (EP2) receptor-protein kinase A signalling cascade. Our results clearly demonstrate that presynaptic GABA/glycine release properties are influenced by the nature and complexity of postsynaptic inhibitory receptor subtypes.

Reduction and prevention of vincristine-induced neuropathic pain symptoms by the non-benzodiazepine anxiolytic etifoxine are mediated by 3α-reduced neurosteroids

The central processing of peripheral nociceptive messages is highly controlled by the activity of local inhibitory networks in the spinal cord and supraspinal centers. Recently, it has been shown that endogenous 3α-reduced neurosteroids (3αNS) exert a significant spinal antinociception by potentiating GABAA receptor function. Because endogenous 3αNS can be produced in many relay structures of the nociceptive system, we tested the potential analgesic efficacy of promoting the production of neurosteroids by using etifoxine (ETX, 50mg/kg i.p.). This prescribed non-benzodiazepine anxiolytic was shown previously to stimulate neurosteroidogenesis in its early step after binding to the mitochondrial translocator protein complex (TSPO). Using an animal model of generalized neuropathic pain resulting from a 2-week treatment with the antitumoral agent vincristine sulfate (VCR, 0.1mg/kg i.p.), we show that injections of ETX (50mg/kg i.p.) given every day reduced the VCR-induced mechanical and thermal pain symptoms but also prevented their appearance, if used in prophylaxia 1week before VCR. Both the curative and preventive effects of ETX on pain symptoms were mediated by the production of 3αNS as demonstrated in animals treated with the enzymatic inhibitor provera (6-medroxyprogesterone acetate; 20mg/kg s.c.). Altogether, this study shows for the first time that promoting 3αNS could be a possible therapeutic strategy to treat neuropathic pain symptoms. Since ETX is already available as an anxiolytic, its use in humans, provided that its analgesic properties are confirmed, could be rapidly considered.

Visceral afferents: What role in post-inflammatory pain?

Several weeks to several months after a bout of inflammation or an infectious event in a visceral organ, while inflammation or infection has resolved, defective nociceptive functions are sometimes still present, characterized by chronic pain symptoms, visceral hyperalgesia and allodynia. Visceral afferents which convey nociceptive messages have been shown to be hyperexcitable in inflammatory states. Only recently, studies have addressed visceral afferent electrical properties and neuroplastic changes in post-inflammatory situations. This review tries to appraise in post-inflammatory hypersensitive states, the most recent advances in the knowledge of visceral afferent inputs, together with in vivo recordings of visceral hyperalgesia and allodynia.

Le dysfonctionnement du « brain-gut »

There is a bidirectional relation between the central nervous system and the digestive tract, i.e., the brain-gut axis. Numerous data argue for a dysfunction of the brain-gut axis in the pathophysiology of irritable bowel syndrome (IBS). Visceral hypersensitivity is a marker of IBS as well as of an abnormality of the brain-gut axis. This visceral hypersensitivity is peripheral and/or central in origin and may be the consequence of digestive inflammation or an anomaly of the nociceptive message treatment at the spinal and/or supraspinal level. Stress is involved in the genesis and maintenance of IBS. Disturbances of the autonomic nervous system are observed in IBS as a consequence of brain-gut axis dysfunction. The contribution of the neurosciences, in particular brain imaging techniques, has contributed to the better understanding of IBS physiopathology. The better knowledge of brain-gut axis dysfunction has therapeutic implications, either through drugs and/or cognitive and behavioral therapies.

Transient Receptor Potential Vanilloid-4 Has a Major Role in Visceral Hypersensitivity Symptoms

The transient receptor potential vanilloid-4 (TRPV4) is an osmosensitive channel that responds to mechanical stimulation. We hypothesized that TRPV4 could be important in visceral nociception and in the development of hypersensitivity. TRPV4 expression was investigated by immunohistochemistry and reverse transcription-polymerase chain reaction. Calcium signaling and patch-clamp studies were performed in dorsal root ganglia (DRG) neurons validating the use of 4alphaPDD as a selective TRPV4 agonist. The effects of TRPV4 activation on visceral nociception were evaluated in mice that received intracolonically TRPV4 agonist (4 alpha-phorbol 12,13-didecanoate [4alphaPDD]) and in TRPV4-deficient mice in which abdominal muscle contractions in response to colorectal distention (CRD) were recorded. Intervertebral injections of TRPV4 or mismatch small interfering RNA (siRNA) were used to specifically down-regulate TRPV4 expression in sensory neurons and to investigate the role of TRPV4 in basal visceral nociception or in protease-activated receptor 2 (PAR(2)) activation-induced visceral hypersensitivity. TRPV4 agonist 4alphaPDD specifically activated a cationic current and calcium influx in colonic projections of DRG neurons and caused dose-dependent visceral hypersensitivity. TRPV4-targeted but not mismatched siRNA intervertebral treatments were effective at reducing basal visceral nociception, as well as 4alphaPDD or PAR(2) agonist-induced hypersensitivity. Effects of the TRPV4 ligand were lost in TRPV4-deficient mice. 4alphaPDD selectively activates TRPV4 in sensory neurons projecting from the colon, and TRPV4 activation causes visceral hypersensitivity. TRPV4 activation is implicated in the nociceptive response to CRD in basal conditions and in PAR(2) agonist-induced hypersensitivity. These results suggest a pivotal role for TRPV4 in visceral nociception and hypersensitivity.

Proteinase-activated receptor 2 (PAR-2) in gastrointestinal and pancreatic pathophysiology, inflammation and neoplasia

Of all the body systems, the gastrointestinal (GI) tract is the most exposed to proteinases. Proteolytic activity must thus be tightly regulated in the face of diverse environmental challenges, because unrestrained or excessive proteolysis leads to pathological GI conditions. The protease-activated receptor-2 (PAR-2) is expressed in numerous cell types within the GI tract, suggesting both multiple functions and numerous modes of receptor activation. Although best known as a pancreatic digestive enzyme, trypsin has also been found in other tissues and various cancers. Of interest, trypsin and PAR-2 act together in an autocrine loop that promotes proliferation, invasion and metastasis in neoplasia through various mechanisms. Trypsin and PAR-2 seem to act both directly and indirectly through activation of other proteinase cascades, including metalloproteinases. PAR-2 activation can participate in inflammatory reactions, be protective to mucosal surfaces, send or inhibit nociceptive messages, modify gut motility or secretory functions, and stimulate cell proliferation and motility. Several studies point to a role for the PARs in disease processes of the GI tract and pancreas ranging from inflammatory bowel disease, symptoms associated with irritable bowel syndrome, pain in pancreatitis, development of colon and other GI cancers, and even infectious colitis. Proteinases should not only be considered from the traditional view as digestive or degradative enzymes in the gut, but additionally as signalling molecules that actively participate in the spectrum of physiology and diseased states of the GI tract.

PKC activation sets an upper limit to the functional plasticity of GABAergic transmission induced by endogenous neurosteroids

The activity of GABAergic inhibitory interneurones located in lamina II of the spinal cord is of fundamental importance for the processing of peripheral nociceptive messages. We have recently shown that 3alpha-hydroxy ring A-reduced pregnane neurosteroids [3alpha5alpha-neurosteroids (3alpha5alphaNS)], potent allosteric modulators of GABA(A) receptors (GABA(A)Rs), are synthesized in the spinal cord and limit thermal hyperalgesia during inflammatory pain. Because changes in the expression of calcium-dependent protein kinases [protein kinase C (PKC)] are observed during pathological pain in the spinal cord, we examined the possible interactions between PKC and 3alpha5alphaNS at synaptic GABA(A)Rs. Using patch-clamp recordings of lamina II interneurones in the spinal cord of 15-20-day-old rats, we showed that synaptic inhibition mediated by GABA(A)Rs and its modulation by 3alpha5alphaNS in lamina II of the spinal cord largely depend on activation of PKC. Our experimental results suggested that activation of PKC locks synaptic GABA(A)Rs in a functional state precluding further positive allosteric modulation by endogenous and exogenous 3alpha5alphaNS. This effect was fully prevented by coadministration of chelerythrin, an inhibitor of PKC. Furthermore, application of chelerythrin alone rendered synaptic GABA(A)Rs hypersensitive to endogenously produced or exogenously applied 3alpha5alphaNS. These findings confirmed that there was a significant production of endogenous 3alpha5alphaNS in lamina II of the spinal cord but also indicated that PKC-dependent phosphorylation processes were tonically activated to control GABA(A)R-mediated inhibition under resting conditions. We therefore can conclude that PKC activation sets an upper limit to the functional plasticity of GABAergic transmission induced by endogenous neurosteroids.

Inflammatory Pain Upregulates Spinal Inhibition via Endogenous Neurosteroid Production

Inhibitory synaptic transmission in the dorsal horn (DH) of the spinal cord plays an important role in the modulation of nociceptive messages because pharmacological blockade of spinal GABAA receptors leads to thermal and mechanical pain symptoms. Here, we show that during the development of thermal hyperalgesia and mechanical allodynia associated with inflammatory pain, synaptic inhibition mediated by GABAA receptors in lamina II of the DH was in fact markedly increased. This phenomenon was accompanied by an upregulation of the endogenous production of 5alpha-reduced neurosteroids, which, at the spinal level, led to a prolongation of GABAA receptor-mediated synaptic currents and to the appearance of a mixed GABA/glycine cotransmission. This increased inhibition was correlated with a selective limitation of the inflammation-induced thermal hyperalgesia, whereas mechanical allodynia remained unaffected. Our results show that peripheral inflammation activates an endogenous neurosteroid-based antinociceptive control, which discriminates between thermal and mechanical hyperalgesia.

Protease-activated receptors and inflammatory hyperalgesia

Recent advances in basic science pointed to a role for proteinases, through the activation of proteinase-activated receptors (PARs) in nociceptive mechanisms. Activation of PAR1, PAR2 and PAR4 either by proteinases or by selective agonists causes inflammation inducing most of the cardinal signs of inflammation: swelling, redness, and pain. Sub-inflammatory doses of PAR2 agonist still induced hyperalgesia and allodynia while PAR2 has been shown to be implicated in the generation of hyperalgesia in different inflammatory models. In contrast, sub-inflammatory doses of PAR1 increases nociceptive threshold, inhibiting inflammatory hyperalgesia, thereby acting as an analgesic agent. PARs are present and functional on sensory neurons, where they participate either directly or indirectly to the transmission and/or inhibition of nociceptive messages. Taken together, the results discussed in this review highlight proteinases as signaling molecules to sensory nerves. We need to consider proteinases and the receptors that are activated by proteinases as important potential targets for the development of analgesic drugs in the treatment of inflammatory pain.

Production of 5alpha-reduced neurosteroids is developmentally regulated and shapes GABA(A) miniature IPSCs in lamina II of the spinal cord.

In lamina II of the spinal dorsal horn, synaptic inhibition mediated by ionotropic GABA(A) and glycine receptors contributes to the integration of peripheral nociceptive messages. Whole-cell patch-clamp recordings were performed from lamina II neurons in spinal cord slices to study the properties of miniature IPSCs (mIPSCs) mediated by activation of GABA(A) and glycine receptors in immature (<30 d) and adult rats. Blockade of neurosteroidogenesis by 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (PK11195), an inhibitor of the peripheral benzodiazepine receptor (PBR), or finasteride, which blocks 5alpha-reductase, accelerated the decay kinetics of GABA(A) receptor-mediated mIPSCs in immature, but not in adult animals. Glycine receptor-mediated mIPSCs remained unaffected under these conditions. These results suggest the presence of a tonic production of 5alpha-reduced neurosteroids in young rats that confers slow decay kinetics to GABA(A) mIPSCs. At all of the ages, selective stimulation of PBR by diazepam in the presence of flumazenil prolonged GABA(A) mIPSCs in a PK11195- and finasteride-sensitive manner. This condition also increased the proportion of mixed GABA(A)/glycine mIPSCs in the immature animals and led to the reappearance of mixed GABA(A)/glycine mIPSCs in the adult. Our results might point to an original mechanism by which the strength of synaptic inhibition can be adjusted locally in the CNS during development and under physiological and/or pathological conditions by controlling the synthesis of endogenous 5alpha-reduced neurosteroids.

Posterior triangular thalamic neurons convey nociceptive messages to the secondary somatosensory and insular cortices in the rat.

This study investigated the responses of posterior triangular (PoT) thalamic neurons to tactile and noxious calibrated stimuli in anesthetized rats. We report here that 41% of PoT units responded to cutaneous stimulation, in most cases, by increasing strongly their firing. Forty-five percent of the responding units were nociceptive specific (NS), 19% were nociceptive nonspecific (NNS), and 36% were tactile. The NS units responded only to frankly noxious stimuli applied to relatively large receptive fields (several parts of the body). They encoded nociceptive temperatures chiefly in 46-50 degrees C ranges. The NNS units resembled NS units but also responded to innocuous stimuli. Tactile units responded chiefly to repeated innocuous stimuli applied to very small receptive fields (one to two fingers or vibrissae). A representative sample of PoT somatosensory neurons, characterized first by their response to innocuous and noxious cutaneous stimuli, were filled with juxtacellular injection of biotin-dextran that made it possible to label adequately the soma, the dendrites, and the entire axon of PoT neurons. We observed that the axons of NS neurons terminated only in secondary somatosensory (S2) cortex, whereas the axons of NNS and tactile neurons projected chiefly to the insular cortex and the amygdala. In conclusion, our results demonstrate a spinal-PoT-S2/insular cortices nociceptive pathway that conveys nociceptive messages arising from lamina I and spinal neurons of deep laminas. Furthermore, our results demonstrate for the first time that projections of PoT neurons are correlated to their physiological properties.

The vanilloid receptor-1 is expressed in rat spinal dorsal horn astrocytes

The vanilloid receptor-1 (TRPV1), expressed by nociceptive fibers, is a transducer of thermal and chemical nociceptive messages. However, endogenous ligands excite TRPV1 receptors localized on central nociceptive terminals and interneurons. Using immunocytochemistry at the ultrastructural level, we show that TRPV1 is also expressed in spinal glial cells characterized as astrocyte by double labeling with glial fibrillary acid protein. Quantification of the labeling shows that the most numerous labeling is neuronal and that 7% of the total TRPV1 labeling is localized in astrocytes. The total absence of staining in TRPV1 knock out mice strongly suggests that true TRPV1 protein is present in astrocytes. The localization of TRPV1-containing astrocytes apposed to nociceptive C-terminals suggests that they may be involved in the control of pain transmission.

Dehydroepiandrosterone potentiates native ionotropic ATP receptors containing the P2X2 subunit in rat sensory neurones.

We have studied the modulatory effect of dehydroepiandrosterone (DHEA), the most abundant neurosteroid produced by glial cells and neurones, on membrane currents induced by the activation of ionotropic ATP (P2X) receptors in neonatal rat dorsal root ganglion neurones. ATP (1 microM) induced three types of currents/responses termed F (fast and transient), S (slowly desensitizing) and M (mixed, sum of F- and S-type responses). DHEA (10 nM to 100 microM) concentration-dependently increased the amplitude of plateau-like currents of S- and M-type responses evoked by submaximal (1 microM) but not saturating (100 microM or 1 mM) concentrations of ATP. Alphabeta-methylene ATP (alphabetame-ATP, 5 microM) also evoked F-, S- and M-type responses, the plateau phases of which were potentiated by lowering external pH (6.3) and by ivermectin (IVM, 3 microM), indicating the presence heteromeric P2X2-containing receptors and possibly of functional native P2X4/6 receptors. There was a strict correlation between the potentiating effects of low pH and DHEA on alphabetame-ATP responses but not between that of IVM and DHEA, suggesting that DHEA selectively modulated P2X2-containing receptors. DHEA also potentiated putative homomeric P2X2 receptor responses recorded in the continuous presence of 1 microM 2'-(or 3')-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP). Our results constitute the first demonstration of a fast potentiation of P2X receptors by a neurosteroid and suggest that DHEA could be an endogenous modulator of P2X2-containing receptors thereby contributing to the facilitation of the detection and/or the transmission of nociceptive messages, particularly under conditions of inflammatory pain where the P2X receptor signalling pathway appears to be upregulated.

Neurobiology of trigeminal pain

The brainstem trigeminal complex integrates somatosensory inputs from orofacial areas and meninges. Recent studies have shown the existence of a double representation of pain within the brainstem, at the level of both caudalis and oralis subnuclei. Noxious messages are mainly conveyed by C-fibers that activate the subnucleus caudalis neurons. These neurons in turn activate the subnucleus oralis whose neurons share similar features with the deep spinal dorsal horn neurons. In contrast with the nearness of the laminar organization of the dorsal horn, the vertical organization of the trigeminal complex offers an easier access for the study of segmental mechanisms of nociceptive processing. This model allowed us to show the existence of subtle NMDA-related mechanisms of segmental nocious processing. The trigeminal complex conveys nociceptive messages to several brainstem and thalamic relays that activate a number of cortical areas responsible for pain sensations and reactions. Cortical processing is sustained by reciprocal interactions with thalamic areas and also by a direct modulation of their pre-thalamic relays. The dysfunction of these multiple modulatory mechanisms probably plays a key role in the pathophysiology of chronic trigeminal pain.

Les douleurs neuropathiques en rhumatologie

Neuropathic pain is a common symptom in rheumatology patients and often occurs in combination with pain related to excessive nociception. A neuropathic mechanism can explain why some patients experience difficulties in describing their pain and fail to respond to conventional analgesic therapy. Identification of a neuropathic component in a patient with a complex pain syndrome requires careful history taking, guided by appropriate questionnaires, a thorough physical evaluation including specific tests, and diagnostic investigations. The examining physician must be familiar with the various abnormalities characteristic of neuropathic pain, such as allodynia, hyperalgesia, and hyperpathia. In the field of rheumatology, neuropathic pain occurs mainly in patients with chronic and postoperative sciatica, autoimmune or inflammatory disease, entrapment syndromes, disease related to alcohol or other toxic substances, diabetes, drug-induced syndromes, and type 1 or 2 complex regional pain syndromes. The pathophysiology of neuropathic pain involves peripheral mechanisms (abnormal ectopic activities, nociceptor downregulation, and abnormal fiber cross-talk), which are often exacerbated by the sympathetic system. Central mechanisms play a role also, particularly in chronic forms (central downregulation, alteration in nociceptive message modulation, central plasticity). These mechanisms explain the effectiveness of the treatments commonly used in neuropathic pain, most are which are not conventional analgesics. In conclusion, to evaluate acute and chronic pain, rheumatologists must become familiar with neuropathic syndromes. In difficult cases, neuropathic pain should be considered and looked for with the goal of initiating a treatment program adapted to the underlying pathophysiological mechanism.

Parabrachial Internal Lateral Neurons Convey Nociceptive Messages from the Deep Laminas of the Dorsal Horn to the Intralaminar Thalamus

This study investigates the physiological properties of parabrachial internal lateral (PBil) neurons that project to the paracentral thalamic (PC) nucleus using antidromic activation and single-unit recording techniques in anesthetized rat. We reported here that most of these neurons responded exclusively to the nociceptive stimulation of large receptive fields with a sustained firing that often outlasted the stimulus up to several minutes. These responses were depressed by intravenous morphine. Our results demonstrated a novel spino-PBil-PC pathway, which transmits nociceptive messages to the PC nucleus, which in turn projects to the prefrontal cortex. Recent clinical imaging studies showed the important participation of prefrontal cortex in emotional response to pain. This spino-PBil-PC pathway may explain how nociceptive messages reach the prefrontal cortex and thus trigger unbearable aversive aspects of pain.

Postsynaptic Signaling via the μ-Opioid Receptor: Responses of Dorsal Horn Neurons to Exogenous Opioids and Noxious Stimulation

Although both pre- and postsynaptic mechanisms have been implicated in the analgesia produced by mu-opioids at the spinal cord, it is not known under what conditions these different controls come into play. Because the mu-opioid receptor (MOR) can be visualized in individual lamina II excitatory interneurons and internalizes into endosomes on ligand binding, we tested whether MOR internalization could be monitored and used to measure postsynaptic MOR signaling. To test whether endogenous opioids modulate these lamina II interneurons during noxious stimulation, we next assessed the magnitude of postsynaptic MOR internalization under a variety of nociceptive conditions. As observed in other systems, we show that MOR internalization in dorsal horn interneurons is demonstrated readily in response to opioid ligands. The MOR internalization is dose-dependent, with a similar dose-response to that observed for opioid-induced increases in potassium conductance. We demonstrate that MOR internalization in lamina II neurons correlates precisely with the extent of analgesia produced by intrathecal DAMGO. These results suggest that MOR internalization provides a good marker of MOR signaling in the spinal cord and that postsynaptic MORs on lamina II interneurons likely participate in the analgesia that is produced by exogenous opioids. We found, however, that noxious stimuli, under normal or inflammatory conditions, did not induce MOR internalization. Thus, endogenous enkephalins and endomorphins, thought to be released during noxious peripheral stimuli, do not modulate nociceptive messages via postsynaptic MORs on lamina II interneurons. We suggest that any endogenous opioids that are released by noxious stimuli target presynaptic MORs or delta-opioid receptors.

The anterior pretectal nucleus participates as a relay station in the glutamate-, but not morphine-induced antinociception from the dorsal raphe nucleus in rats

The anterior pretectal nucleus (APtN) and the dorsal raphe nucleus (DRN) are involved in descending pathways that control noxious inputs to the spinal cord and participate in the normal physiological response to noxious stimulation. Evidence has also been provided for the involvement of the APtN acting as a relay station through which the DRN partly modulates spinal nociceptive messages. In the present study, the effects of microinjecting glutamate or morphine into the DRN on the latency for the tail withdrawal reflex after noxious heating of the skin were examined in rats in which hyperbaric lidocaine (5%), naloxone (a non-selective opioid antagonist) or methiothepin (a non-selective 5-HT 1 antagonist) was previously microinjected into the APtN. Microinjection of glutamate (38 nmol/0.25 μl) into the DRN evoked strong but short-lasting antinociception that was fully inhibited by the previous administration of lidocaine (0.25 μl), naloxone (2.7 nmol/0.25 μl), or methiothepin (1 nmol/0.25 μl). A smaller dose of methiothepin (0.5 nmol/0.25 μl) significantly reduced the effect of glutamate. Microinjection of morphine (7.5 nmol/0.25 μl) into the DRN evoked strong and long-lasting antinociception that was not significantly changed by previous microinjection of lidocaine into the APtN. These results confirm that APtN integrity is at least in part necessary for the antinociceptive effects of stimulating the DRN, and that at least opioid and 5-HT1 mechanisms in the APtN participate as neuromodulators in the DRN–APtN connection. The results demonstrate that the antinociceptive effects of stimulating the DRN–APtN path depend on the activation of cell bodies in the DRN that can be excited by the local administration of glutamate, but not morphine. The study also further supports the notion that the DRN is involved in both descending and ascending pain inhibitory systems.

Mechanisms of pain in peripheral neuropathy.

Over the last few years, the mechanisms of pain due to peripheral nerve injury have been the subject of extensive clinical and fundamental investigation. Several types of peripheral mechanisms have been described in animal models of peripheral nerve injury. Abnormal (ectopic) neuronal activity has been reported in primary afferents and in the dorsal root ganglion, and appears related to dysregulation of the synthesis and/or the functioning of sodium channels (notably the tetrodotoxin-resistant channel). Fiber interactions (ephaptic or cross-excitation), nociceptor sensitization and sympathetic sensory coupling may also be involved in some cases. Peripheral nerve lesions can also induce central changes; this has essentially been investigated at the spinal cord level in animals. Three major types of modifications could induce a pathologic activation of central nociceptive neurons: modification of the modulatory controls of the transmission of nociceptive messages; anatomic reorganization (neuroplasticity) of the central nociceptive neurons, and thus their pathologic activation; and central sensitization (hyperexcitability) of nociceptive neurons to produce modifications of their electrophysiologic properties. Central sensitization probably depends critically on intracellular changes induced by the activation of N-methyl-D-aspartate (NMDA) receptors by excitatory amino acids released by primary afferents. Due to the multiplicity of mechanisms, it is unlikely that neuropathic pain corresponds to a unique entity. Each of the painful symptoms may correspond to distinct mechanisms and thus respond to specific treatments.