Future perspectives: the next fifty years of the International Association for the Study of Pain.

ABSTRACT: The International Association for the Study of Pain (IASP) has become the leading professional association dedicated to promoting pain research and management. Through its many activities, including research funding, educational programs, advocacy initiatives, and global collaborations, the Association has significantly contributed to the understanding and treatment of pain. Looking into the future, the IASP is determined to continue its mission of reducing the burden of pain on individuals and societies worldwide. Here, we explore how current and past activities of the IASP will shape the future of pain research, treatment, education, and advocacy as well as provide a valuable service to its members across the world.

Mild Social Stress in Mice Produces Opioid-Mediated Analgesia in Visceral but Not Somatic Pain States.

Visceral pain has a greater emotional component than somatic pain. To determine if the stress-induced analgesic response is differentially expressed in visceral versus somatic pain states, we studied the effects of a mild social stressor in either acute visceral or somatic pain states in mice. We show that the presence of an unfamiliar conspecific mouse (stranger) in an adjacent cubicle of a standard transparent observation box produced elevated plasma corticosterone levels compared with mice tested alone, suggesting that the mere presence of a stranger is stressful. We then observed noxious visceral or somatic stimulation-induced nociceptive behavior in mice tested alone or in mildly stressful conditions (ie, beside an unfamiliar stranger). Compared with mice tested alone, the presence of a stranger produced a dramatic opioid-dependent reduction in pain behavior associated with visceral but not somatic pain. This social stress-induced reduction of visceral pain behavior relied on visual but not auditory/olfactory cues. These findings suggest that visceral pain states may provoke heightened responsiveness to mild stressors, an effect that could interfere with testing outcomes during simultaneous behavioral testing of multiple rodents. PERSPECTIVE: In mice, mild social stress due to the presence of an unfamiliar conspecific mouse reduces pain behavior associated with noxious visceral but not somatic stimulation, suggesting that stress responsiveness may be enhanced in visceral pain versus somatic pain states.

eIF2α phosphorylation controls thermal nociception.

A response to environmental stress is critical to alleviate cellular injury and maintain cellular homeostasis. Eukaryotic initiation factor 2 (eIF2) is a key integrator of cellular stress responses and an important regulator of mRNA translation. Diverse stress signals lead to the phosphorylation of the α subunit of eIF2 (Ser51), resulting in inhibition of global protein synthesis while promoting expression of proteins that mediate cell adaptation to stress. Here we report that eIF2α is instrumental in the control of noxious heat sensation. Mice with decreased eIF2α phosphorylation (eIF2α+/S51A) exhibit reduced responses to noxious heat. Pharmacological attenuation of eIF2α phosphorylation decreases thermal, but not mechanical, pain sensitivity, whereas increasing eIF2α phosphorylation has the opposite effect on thermal nociception. The impact of eIF2α phosphorylation (p-eIF2α) on thermal thresholds is dependent on the transient receptor potential vanilloid 1. Moreover, we show that induction of eIF2α phosphorylation in primary sensory neurons in a chronic inflammation pain model contributes to thermal hypersensitivity. Our results demonstrate that the cellular stress response pathway, mediated via p-eIF2α, represents a mechanism that could be used to alleviate pathological heat sensation.

Translational control of nociception via 4E-binding protein 1.

Activation of the mechanistic/mammalian target of rapamycin (mTOR) kinase in models of acute and chronic pain is strongly implicated in mediating enhanced translation and hyperalgesia. However, the molecular mechanisms by which mTOR regulates nociception remain unclear. Here we show that deletion of the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a major mTOR downstream effector, which represses eIF4E activity and cap-dependent translation, leads to mechanical, but not thermal pain hypersensitivity. Mice lacking 4E-BP1 exhibit enhanced spinal cord expression of neuroligin 1, a cell-adhesion postsynaptic protein regulating excitatory synapse function, and show increased excitatory synaptic input into spinal neurons, and a lowered threshold for induction of synaptic potentiation. Pharmacological inhibition of eIF4E or genetic reduction of neuroligin 1 levels normalizes the increased excitatory synaptic activity and reverses mechanical hypersensitivity. Thus, translational control by 4E-BP1 downstream of mTOR effects the expression of neuroligin 1 and excitatory synaptic transmission in the spinal cord, and thereby contributes to enhanced mechanical nociception.

Pathophysiology of visceral pain / Fisiopatologia da dor visceral

BACKGROUNDS AND OBJECTIVES: Visceral pain shows many pathophysiological properties that make this form of pain unique, not only because of the clinical properties of the sensation but also because the neurobiological mechanisms that mediate the sensory process. This study aimed at reviewing the pathophysiology of visceral pain. CONTENTS: The activation and sensitization of visceral nociceptors are heavily influenced by the secretory and motor properties of the microenvironment where the sensory receptors are located. In some cases, epithelial cells can play a direct role in the activation of primary sensory neurons. Subclinical alterations of the visceral epithelium can contribute to enhanced visceral sensitivity. Central hypersensitivity induced by visceral activation can be caused by mobilization of AMPA receptors from the cytosol to the membrane of nociceptive neurons. In addition, functional pain syndromes, such as the Irritable Bowel Syndrome, could be triggered or maintained by hormonal alterations, particularly those involving sex hormones such as estrogen. CONCLUSION: The neurobiological mechanisms that mediate visceral pain are sufficiently unique to preclude interpreting visceral pain conditions purely as a direct extrapolation of what we know about somatic pain. The functional properties of visceral nociceptors are different from those of their somatic counterparts and the microenvironment where visceral nociceptors are located, and especially the motor and secretory functions of organs like the gut, play a key role in the activation and sensitization of visceral sensory receptors. .

JUSTIFICATIVA E OBJETIVOS: A dor visceral apresenta muitas propriedades fisiopatológicas que fazem dela única, não apenas devido às propriedades clínicas da sensação, mas também devido aos mecanismos neurobiológicos que mediam o processo sensorial. O objetivo deste estudo foi rever a fisiopatologia da dor visceral. CONTEÚDO: A ativação e a sensibilização dos nociceptores viscerais são altamente influenciadas pelas propriedades secretórias e motoras do microambiente onde os receptores sensoriais estão localizados. Em alguns casos, as células epiteliais podem ter uma função direta na ativação de neurônios sensoriais primários. Alterações subclínicas do epitélio visceral podem contribuir para o aumento da sensibilidade visceral. A hipersensibilidade central induzida pela ativação visceral pode ser causada pela mobilização de receptores AMPA do citosol para a membrana de neurônios nociceptivos. Além disso, síndromes dolorosas funcionais, como a Síndrome do Intestino Irritável, podem ser provocadas ou mantidas por alterações hormonais, especialmente aquelas envolvendo hormônios sexuais, como o estrógeno. CONCLUSÃO: Os mecanismos neurobiológicos que mediam a dor visceral são suficientemente únicos para excluir a possibilidade de interpretar condições de dor visceral puramente como a extrapolação direta do que sabemos sobre dor somática. As propriedades funcionais dos nociceptores viscerais são diferentes das dos nociceptores somáticos e o microambiente onde os nociceptores viscerais estão localizados, e principalmente as funções motoras e secretórias de órgãos como o intestino, têm função importante na ativação e sensibi...

Stimulation of cutaneous low threshold mechanoreceptors in mice after intracolonic capsaicin increases spinal c-Fos labeling in an NKCC1-dependent fashion.

UNLABELLED: Stimulation of peripheral nociceptors results in increased c-Fos labeling in spinal cord regions associated with nociceptive processing. Accordingly, intracolonic capsaicin, which generates robust secondary (referred) allodynia on the abdomen of mice, also causes an increased spinal c-Fos labeling. In naïve rodents, low intensity innocuous stimulation does not affect c-Fos labeling in spinal nociceptive regions. However, after persistent noxious input, low intensity stimulation of the inflamed region further enhances c-Fos labeling, suggesting that low threshold mechanosensitive fibers gain access to the nociceptive channel after persistent inflammation. We have previously proposed that afferent activity in low threshold sensory fibers activates nociceptive sensory fibers through Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) -mediated enhanced primary afferent depolarization. Here, we show that intracolonic capsaicin enhances spinal c-Fos labeling and secondary allodynia in an NKCC1-dependent manner. Furthermore, we demonstrate that gently brushing the abdomen, the region of secondary allodynia, further increased spinal c-Fos levels, an effect that can be prevented by spinal NKCC1 blockade. These findings provide evidence that increased NKCC1 activity contributes to secondary allodynia and that innocuous touch can access the nociceptive channel in part through enhanced NKCC1 activity. PERSPECTIVE: While touch normally soothes acute pain, we demonstrate that following peripheral inflammation, touch evokes pain (allodynia) through the switching of a normally inhibitory spinal pathway into an excitatory pathway. Activation of low threshold mechanoreceptors activates spinal nociceptive neurons following inflammation-induced enhancement of NKCC1 expression, as measured by spinal c-Fos labeling.

PKMζ is essential for spinal plasticity underlying the maintenance of persistent pain.

BACKGROUND: Chronic pain occurs when normally protective acute pain becomes pathologically persistent. We examined here whether an isoform of protein kinase C (PKC), PKMζ, that underlies long-term memory storage in various brain regions, also sustains nociceptive plasticity in spinal cord dorsal horn (SCDH) mediating persistent pain. RESULTS: Cutaneous injury or spinal stimulation produced persistent increases of PKMζ, but not other atypical PKCs in SCDH. Inhibiting spinal PKMζ, but not full-length PKCs, reversed plasticity-dependent persistent painful responses to hind paw formalin and secondary mechanical hypersensitivity and SCDH neuron sensitization after hind paw capsaicin, without affecting peripheral sensitization-dependent primary heat hypersensitivity after hind paw capsaicin. Inhibiting spinal PKMζ, but not full-length PKCs, also reversed mechanical hypersensitivity in the rat hind paw induced by spinal stimulation with intrathecal dihydroxyphenylglycine. Spinal PKMζ inhibition also alleviated allodynia 3 weeks after ischemic injury in rats with chronic post-ischemia pain (CPIP), at a point when allodynia depends on spinal changes. In contrast, spinal PKMζ inhibition did not affect allodynia in rats with chronic contriction injury (CCI) of the sciatic nerve, or CPIP rats early after ischemic injury, when allodynia depends on ongoing peripheral inputs. CONCLUSIONS: These results suggest spinal PKMζ is essential for the maintenance of persistent pain by sustaining spinal nociceptive plasticity.

Presynaptic alpha2-GABAA receptors in primary afferent depolarization and spinal pain control.

Spinal dorsal horn GABA(A) receptors are found both postsynaptically on central neurons and presynaptically on axons and/or terminals of primary sensory neurons, where they mediate primary afferent depolarization (PAD) and presynaptic inhibition. Both phenomena have been studied extensively on a cellular level, but their role in sensory processing in vivo has remained elusive, due to inherent difficulties to selectively interfere with presynaptic receptors. Here, we address the contribution of a major subpopulation of GABA(A) receptors (those containing the α2 subunit) to spinal pain control in mice lacking α2-GABA(A) receptors specifically in primary nociceptors (sns-α2(-/-) mice). sns-α2(-/-) mice exhibited GABA(A) receptor currents and dorsal root potentials of normal amplitude in vitro, and normal response thresholds to thermal and mechanical stimulation in vivo, and developed normal inflammatory and neuropathic pain sensitization. However, the positive allosteric GABA(A) receptor modulator diazepam (DZP) had almost completely lost its potentiating effect on PAD and presynaptic inhibition in vitro and a major part of its spinal antihyperalgesic action against inflammatory hyperalgesia in vivo. Our results thus show that part of the antihyperalgesic action of spinally applied DZP occurs through facilitated activation of GABA(A) receptors residing on primary nociceptors.

Local activation of cannabinoid CB1 receptors in the urinary bladder reduces the inflammation-induced sensitization of bladder afferents.

BACKGROUND: Systemic administration of cannabinoid agonists is known to reduce pain induced by bladder inflammation and to modulate cystometric parameters in vivo. We have previously reported that intravesical administration of a cannabinoid agonist reduces the electrical activity of bladder afferents under normal conditions. However, the effects of local activation of bladder cannabinoid receptors on afferent activity during inflammation are unknown. This study was aimed to assess the effects of intravesical administration of a cannabinoid agonist on the discharges of afferent fibers in inflamed bladders ex vivo. We also characterized the expression of CB1 receptors in the bladder and their localization and co-expression with TRPV1, a marker of nociceptive afferents. RESULTS: Compared to untreated animals, afferent fiber activity in inflamed bladders was increased for intravesical pressures between 10 and 40 mmHg. Local treatment with a non selective cannabinoid agonist (AZ12646915) significantly reduced the afferent activity at intravesical pressures above 20 mmHg. This effect was blocked by AM251 but not by AM630 (selective for CB1 and CB2 respectively). Finally, CB1 was co-expressed with TRPV1 in control and inflamed bladders. CONCLUSION: These results demonstrate that sensitization of bladder afferents induced by inflammation is partly suppressed by intravesical activation of cannabinoid receptors, an effect that appears to be mediated by CB1 receptors. Also, TRPV1 positive fibers were found to co-express CB1, supporting the hypothesis of a direct action of the cannabinoid agonist on nociceptive afferents. Taken together, these results indicate a peripheral modulation by the cannabinoid system of bladder hypersensitivity during inflammation.

Role of the NKCC1 co-transporter in sensitization of spinal nociceptive neurons.

The Na(+), K(+), 2Cl(-) co-transporter type 1 (NKCC1) plays a pivotal role in hyperalgesia associated with inflammatory stimuli. NKCC1 contributes to maintain high [Cl(-)](i) in dorsal root ganglia (DRG) neurons which cause primary afferent depolarization (PAD) when GABA(A) receptors are activated. Enhanced GABA-induced depolarization, through increased NKCC1 activity, has been hypothesized to produce orthodromic spike activity of sufficient intensity to account for touch-induced pain. In the present study, we investigate this hypothesis using in vivo electrophysiology on rat dorsal horn neurons; the effects of spinal blockade of NKCC1 on intraplantar capsaicin-induced sensitization of dorsal horn neurons were examined. Single wide dynamic range (WDR) and nociceptive specific (NS) neuron activity in the dorsal horn was recorded using glass microelectrodes in anesthetized rats. Dorsal horn neurons with a receptive field on the plantar surface of the hindpaw were studied. Neuronal responses to mechanical stimuli (brush, von Frey filaments) were recorded ten minutes before intraplantar injection of 0.3 ml 0.1% capsaicin (CAP), 40 min after CAP and 15 min after local application of the NKCC1 blocker bumetanide (BTD; 500 µM) on the spinal cord. After CAP, low and high threshold stimulation of the cutaneous receptive field produced a significant enhancement in spike frequency over pre-CAP values in both WDR and NS neurons. Spinal BTD application reduced the spike frequency to baseline levels as well as attenuated the CAP-induced increases in background activity. Our data support the hypothesis that NKCC1 plays an important role in the sensitization of dorsal horn neurons following a peripheral inflammatory insult.

Stimulation of dorsal root afferents increases the excitability of ascending sensory axons in the isolated spinal cord of mature mice.

The phenomenon of windup has often been used to assess excitability increases of spinal neurons induced by repetitive stimulation of nociceptive afferents. Windup has been studied in individual spinal cord neurons and in spinal motor reflexes neither of which accurately reflect the forward transmission of nociceptive signals to the brain. In addition, most in vitro studies of spinal windup have been conducted on immature or juvenile animals and it is challenging to extrapolate these results to the adult spinal cord. In the present study, we have used an in vitro whole spinal cord preparation from functionally mature mice (up to 8 weeks old) to record windup activity in ascending axons in the mid-thoracic region evoked by electrical stimulation of a lumbar or sacral dorsal root. Windup responses were observed in axons in the ipsi- and contralateral dorsolateral funiculus (iDLF and cDLF) and in the contralateral ventrolateral funiculus (cVLF). No windup responses were evoked in postsynaptic axons of the ipsilateral dorsal columns (iDC) and no postsynaptic responses were elicited in the ipsilateral ventrolateral funiculus (iVLF) or contralateral dorsal columns (cDC). Between 40% and 45% of all axons in the DLF and cVLF that responded to a single dorsal root stimulus also showed windup. The NMDA receptor antagonist MK-801 reversibly blocked such windup responses. These results illustrate that windup can be consistently recorded from ascending pathways in the mature spinal cord in vitro but also show that windup can only be elicited in a proportion of sensory axons projecting through some, but not all, ascending spinal cord pathways.

Role of RVM neurons in capsaicin-evoked visceral nociception and referred hyperalgesia.

Most forms of visceral pain generate intense referred hyperalgesia but the mechanisms of this enhanced visceral hypersensitivity are not known. The on-cells of the rostral ventromedial medulla (RVM) play an important role in descending nociceptive facilitation and can be sensitized to somatic mechanical stimulation following peripheral nerve injury or hindpaw inflammation. Here we have tested the hypothesis that visceral noxious stimulation sensitizes RVM ON-like cells, thus promoting an enhanced descending facilitation that can lead to referred visceral hyperalgesia. Intracolonic capsaicin instillation (ICI) was applied to rats in order to create a hyperalgesic state dependent on noxious visceral stimulation. This instillation produced acute pain-related behaviors and prolonged referred hyperalgesia that were prevented by the RVM microinjection of AP5, an NMDA selective antagonist. In electrophysiological experiments, ON-like RVM neurons showed ongoing spontaneous activity following ICI that lasted for approximately 20 min and an enhanced responsiveness to von Frey and heat stimulation of the hindpaw and to colorectal distention (CRD) that lasted for at least 50 min post capsaicin administration. Moreover, ON-like cells acquired a novel response to CRD and responded to heat stimulation in the innocuous range. OFF-like neurons responded to capsaicin administration with a brief (<5 min) inhibition of activity followed by an enhanced inhibition to noxious stimulation and a novel inhibition to innocuous stimulation (CRD and heat) at early time points (10 min post capsaicin). These results support the hypothesis that noxious visceral stimulation may cause referred hypersensitivity by promoting long-lasting sensitization of RVM ON-like cells.

Estrogen-dependent changes in visceral afferent sensitivity.

Many forms of chronic pain are more prevalent in women and this is interpreted as the consequence of a direct role of estrogens in the modulation of pain perception. Some functional pain states, i.e. those without a clear and demonstrable pathology, are also more prevalent in women and the pain in these conditions is also modulated by hormonal variations during the menstrual cycle. Increased pain sensitivity is commonly interpreted as the consequence of peripheral or central hyperexcitability of nociceptive pathways. Therefore a role has been suggested for estrogen in the modulation of the excitability of nociceptive afferents and central neurons. The literature on the sign of this modulation is not uniform, with reports pointing to estrogen as either pro- or anti-nociceptive. In our hands, a permanent reduction in the levels of estrogen, such as that induced by surgical ovariectomy (OVX) generates a hyperalgesic state of slow onset and long duration that can be prevented or reversed by exogenous administration of estrogen. The hyperalgesia is characterized by mechanical and thermal hyperalgesia in the abdominal and pelvic regions as well as by visceral hypersensitivity. The possible role of estrogen in the prevention of chronic painful states is discussed.

Pain: friend or foe? A Neurobiologic perspective: the 2008 Bonica Award Lecture.

Pain is a protective sensation, but it can also be a burden without any useful value. Pain as a friend warns of impending damage and protects the body from injury. Pain as a foe is a useless sensation that makes the underlying problem worse and becomes a disease in its own right. Mechanistically, the systems that mediate good pain and bad pain are often the same, with bad pain being the result of such mechanisms being triggered inappropriately, by irrelevant stimuli or with a time course and intensity disproportionate to the originating cause. We are beginning to know more about the neurobiology of bad pain. The relevant mechanisms are often linked to dysfunction or disease of the nervous system, either of the peripheral nerves or of the central nervous system itself. For example, under normal conditions, activity in large, myelinated A[beta]-fibers inhibits nociceptive primary afferent inputs to the central nervous system. However, in inflammatory and neuropathic conditions, these actions are reversed, leading to touch-evoked pain or tactile allodynia. The mechanism responsible for this reversal is a change in the synaptic actions of [gamma]-aminobutyric acid that switches from being an inhibitory neurotransmitter to an excitatory one. Our challenge was to devise methods for pain relief based on elimination of the useless aspects of pain and the restoration of the protective qualities of normal pain sensation.

Spinal cord hyperexcitability and its role in pain and hyperalgesia.

Sensitization of spinal cord nociceptive neurons is commonly interpreted as the cause for the hypersensitivity that characterizes chronic pain states in humans. However, in spite of much basic research in this area it has not been possible to demonstrate a direct link between the hyperexcitability of spinal cord neurons observed experimentally and the underlying mechanism of a chronic pain state. The word sensitization is also used in the literature with various and different meanings from the qualification of a cellular process of enhanced excitability at synaptic level to the characteristics of a chronic pain syndrome. In this article the various meanings of sensitization are described and the relevance of the hyperexcitability of spinal cord neurons to the generation of clinically relevant pain states is discussed. A proposal is made to restrict the use of the word sensitization to the cellular process of enhanced excitability observed experimentally after repetitive stimulation of nociceptive afferents. Caution is also recommended when associating neuronal sensitization in the spinal cord with the mechanisms of chronic pain conditions.