Hans-Georg Schaible

Mechanisms of Pain in Arthritis

Abstract: Inflammation in the joint causes peripheral sensitization (increase of sensitivity of nociceptive primary afferent neurons) and central sensitization (hyperexcitability of nociceptive neurons in the central nervous system). The processes of sensitization are thought to be the basis of arthritic pain that appears as spontaneous pain (joints at rest) and hyperalgesia (augmented pain response on noxious stimulation and pain on normally nonpainful stimulation). Sensitization also facilitates efferent neuronal processes through which the nervous system influences the inflammatory process. Peripheral sensitization is produced by the action of inflammatory mediators such as bradykinin, prostaglandins, neuropeptides, and cytokines which activate corresponding receptors in proportions of nerve fibers. In addition, the expression of receptors, for example, bradykinin and neurokinin 1 receptors, is upregulated during inflammation. The development of hyperexcitability of spinal cord neurons is produced by various transmitter/receptor systems that constitute and modulate synaptic activation of the neurons. The key transmitter is glutamate that activates N‐methyl‐d‐aspartate (NMDA) and non‐NMDA receptors on spinal cord neurons. Blockade of these receptors prevents and reduces central sensitization. Excitatory neuropeptides (substance P and calcitonin gene‐related peptide) further central sensitization. Central sensitization also is facilitated by mediators that have complex actions (e.g., prostaglandin E2). Spinal PGE2 binds to receptors at presynaptic endings of primary afferent neurons (thus influencing synaptic release) and to receptors on postsynaptic spinal cord neurons. The administration of PGE2 to the spinal cord surface produces changes of responsiveness of spinal neurons similar to peripheral inflammation, and spinal indomethacin to the spinal cord attenuates development of hyperexcitability significantly.

Effects of antagonists to high-threshold calcium channels upon spinal mechanisms of pain, hyperalgesia and allodynia.

Abstract High‐threshold voltage‐dependent calcium channels enable calcium ions to enter neurons upon depolarization and thereby influence synaptic mediator/receptor systems, membrane excitability levels, second and third messenger concentration, and gene expression. These phenomena underlie several processes including those of normal nociception and of hyperalgesia and allodynia. The present article deals with the role of spinal L‐, N‐ and P/Q‐type calcium channels in short‐lasting nociception as well as in the hyperalgesia and allodynia elicited by chemical irritants of peripheral nociceptors, inflammatory and mechanical lesions of peripheral tissues, and lesions of peripheral nerves. The studies summarized herein are based on the spinal delivery of specific antagonists to high‐threshold calcium channels, and reveal that blockade of L‐type, P/Q‐type and, particularly, N‐type channels can prevent, attenuate, or both, subjective pain as well as primary and/or secondary hyperalgesia and allodynia in a variety of experimental and clinical conditions.

A de novo gain-of-function mutation in SCN11A causes loss of pain perception

The sensation of pain protects the body from serious injury. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Nav1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system. Mutant Nav1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception.

Is there a correlation between spreading depression, neurogenic inflammation, and nociception that might cause migraine headache?

The time course of propagation of scotoma and blood flow changes during migraine aura parallels the phenomenon of cortical spreading depression (CSD). It was proposed that CSD generates a sterile neurogenic inflammation in the meninges, which may then lead to the activation or sensitization of nociceptors, thus generating headache. We performed rat experiments in which the effect of CSD on plasma extravasation in the dura mater and on neuronal activity in deep laminae of the trigeminal nucleus was assessed in vivo. CSD did not alter dural plasma extravasation measured by means of bovine serum albumin–coupled flourescein (n = 17 rats) compared to the CSD‐free contralateral side. In an in vitro model, the application of KCl to the dura at concentrations extracellularly found during CSD did not alter the release of calcitonin gene–related peptide and prostaglandin E2 from the dura. In 33 rats, neither single CSDs nor a series of CSDs altered ongoing neuronal activity or mechanical and/or thermal sensitivity of the deeply located neurons to stimulation of their receptive fields in the dura mater. These results are at variance with data that showed increased c‐Fos labeling in superficial laminae of the trigeminal nucleus following CSD. They do not suggest that CSD initiates migraine headache via neurogenic inflammation. Ann Neurol 2001;49:7–13

Antinociceptive effects of tumor necrosis factor α neutralization in a rat model of antigen-induced arthritis: Evidence of a neuronal target

OBJECTIVE The reduction of pain in the course of antiinflammatory therapy can result from an attenuation of the inflammatory process and/or from the neutralization of endogenous mediators of inflammation that act directly on nociceptive neurons. The purpose of this study was to investigate whether analgesic effects of the neutralization of tumor necrosis factor alpha (TNFalpha) are due to an attenuation of inflammation or whether direct neuronal effects significantly contribute to pain relief in the course of therapy. METHODS Locomotor and pain-related behavior and histology were assessed in rats with chronic antigen-induced arthritis (AIA) in the knee joint, and the rats were treated with systemic saline, etanercept, or infliximab. The expression of TNF receptors (TNFRs) in dorsal root ganglia was measured using immunohistochemical analysis and polymerase chain reaction. Action potentials were recorded from afferent Adelta fibers and C fibers of the medial knee joint nerve, and etanercept and infliximab were injected intraarticularly into normal or inflamed knee joints (AIA or kaolin/carrageenan-induced inflammation). RESULTS In rats with AIA, both etanercept and infliximab significantly decreased inflammation-induced locomotor and pain-related behavior, while joint swelling was only weakly attenuated and histomorphology still revealed pronounced inflammation. A large proportion of dorsal root ganglion neurons showed TNFRI- and TNFRII-like immunoreactivity. Intraarticular injection of etanercept reduced the responses of joint afferents to mechanical stimulation of the inflamed joint starting 30 minutes after injection, but had no effect on responses to mechanical stimulation of the uninflamed joint. CONCLUSION Overall, these data show the pronounced antinociceptive effects of TNFalpha neutralization, thus suggesting that reduction of the effects of TNFalpha on pain fibers themselves significantly contributes to pain relief.

The Effects of NMDA Antagonists on Neuronal Activity in Cat Spinal Cord Evoked by Acute Inflammation in the Knee Joint

In α‐chloralose‐anaesthetized, spinalized cats we examined the effects of NMDA antagonists on the discharges of 71 spinal neurons which had afferent input from the knee joint. These neurons were rendered hyperexcitable by acute arthritis in the knee induced by kaolin and carrageenan. They were located in the deep dorsal and ventral horn and some of them had ascending axons. The N‐methyl‐d‐aspartate (NMDA) antagonists ketamine and d‐2‐amino‐5‐phosphonovalerate (AP5), were administered ionophoretically, and ketamine was also administered intravenously. In some of the experiments the antagonists were tested against the agonists NMDA and quisqualate. The effects of the NMDA antagonists consisted of a significant reduction in the resting activity of neurons and/or the responses of the same neurons to mechanical stimulation of the inflamed knee. Intravenous ketamine was most effective in suppressing the resting and mechanically evoked activity in 25 of 26 neurons tested. Ionophoretically applied ketamine had a suppressive effect in 11 of 21 neurons, and AP5 decreased activity in 17 of 24 cells. The reduction in the resting and/or the mechanically evoked discharges was achieved with doses of the antagonists which suppressed the responses to NMDA but not those to quisqualate. These results suggest that NMDA receptors are involved in the enhanced responses and basal activity of spinal neurons induced by inflammation in the periphery.

Sensitization of articular afferents to mechanical stimuli by bradykinin.

In 18 cats anaesthetized with alpha-chloralose, we recorded from thin myelinated and unmyelinated articular afferents of the medial articular nerve of the knee joint. Bradykinin was injected intra-arterially close to the knee, alone and in combination with prostaglandin E2 (PGE2), and changes of the responses of single afferents to movements of the knee were monitored. Bradykinin changed the mechanosensitivity in 20 of 28 afferents inducing movement sensitivity in initially unresponsive units, lowering the threshold for movements in high-threshold afferents and/ or enhancing pre-existing responses to innocuous and/or noxious joint movements in low and high threshold units. Also the application of PGE2 and bradykinin within a short interval sensitized the majority of these afferents, and in about 50% of the afferents the effect of the combination was superior to those induced by the single substances. We conclude that the inflammatory mediator bradykinin is able to sensitize articular afferents for movement stimuli and that PGE2 may enhance this effect. It is suggested that in arthritis inflammatory mediators act synergistically in the initiation and stabilization of the increased mechanosensitivity of slowly conducting articular afferents.

The cytokine TNFα increases the proportion of DRG neurones expressing the TRPV1 receptor via the TNFR1 receptor and ERK activation

TNFalpha is involved in the generation of hyperalgesia in pathological states such as neuropathy and inflammation. The pronociceptive action of TNFalpha may be mediated at least in part by activation of the TRPV1 receptor which transduces heat stimuli in primary nociceptive afferents and mediates thermal hyperalgesia. In the present study, we investigated in cultured dorsal root ganglion (DRG) neurones, the somata of primary afferent fibres, whether TNFalpha increases TRPV1 receptor expression. We found that long-term exposure of DRG neurones of both rat and mouse to TNFalpha significantly increased the proportion of DRG neurones expressing TRPV1 receptor-like immunoreactivity. This TNFalpha effect was abolished in mice DRG neurones when DRG cultures were obtained from tnfr1/2-/- and tnfr1-/-, but not from tnfr2-/- mice. Furthermore, we found that activation of ERK but not of p38 kinase or cyclooxygenases is critically involved in the TNFalpha-induced increase of TRPV1 receptor expression.

Mechanisms of Chronic Pain in Osteoarthritis

Pain is a major clinical problem of osteoarthritis (OA). Recently, OA has been thought to be a disease of the whole joint with both destruction of cartilage and inflammatory components such as synovitis and bone marrow lesions. Clinical studies have documented a significant inflammatory soft tissue contribution to the severity and frequency of OA pain. Both clinical and experimental studies have provided evidence for the sensitization of pain pathways during OA, involving pronounced changes in joint nociceptors and changes of the nociceptive processing in the spinal cord, brainstem, and thalamocortical system. Additionally, evidence has been provided for neuropathic pain components in OA models. Concerning molecular mechanisms of OA pain and potential options for pain therapy, studies on nerve growth factor, cytokines, sodium channel blockers, hyaluronic acid preparations, and others are addressed in this review.

Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines

The peripheral nociceptor is an important target of pain therapy because many pathological conditions such as inflammation excite and sensitize peripheral nociceptors. Numerous ion channels and receptors for inflammatory mediators were identified in nociceptors that are involved in neuronal excitation and sensitization, and new targets, beyond prostaglandins and cytokines, emerged for pain therapy. This review addresses mechanisms of nociception and focuses on molecules that are currently favored as new targets in drug development or that are already targeted by new compounds at the stage of clinical trials - namely the transient receptor potential V1 receptor, nerve growth factor, and voltage-gated sodium channels - or both.