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

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.

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

Unlabelled: 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.

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.

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.

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.

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.

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).

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.

A role for extracellular signal-regulated kinases 1 and 2 in the maintenance of persistent mechanical hyperalgesia in ovariectomized mice.

Mitogen-activated protein kinases (MAPKs) are important signaling factors in many cellular processes including cell proliferation and survival during development and synaptic plasticity induced by acute nociception in the adult. There is extensive evidence for the involvement of members of the MAPK family, the extracellular signal-regulated kinases 1 and 2 (ERKs 1/2), in the development of acute inflammatory somatic and visceral pain, but their role in the maintenance of chronic pain states is unknown. We have previously shown that ovariectomy of adult mice (OVX) generates a persistent and estrogen-dependent abdominal hyperalgesic state that lasts for several months and is not related to a persistent nociceptive afferent input.

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.

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.

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.

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.

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.

Cannabinoid CB1 receptors are expressed in the mouse urinary bladder and their activation modulates afferent bladder activity.

Pharmacological studies have indirectly shown the possible presence of cannabinoid receptors in the urinary bladder and their potential role in reducing bladder inflammatory pain. However, the localization of cannabinoid receptors in the urinary bladder remains unknown and there are no published data on the effects of cannabinoids on the sensory system of the bladder. The present study was performed to evaluate the expression of the cannabinoid CB(1) receptors in the mouse urinary bladder and to assess their co-localization with the purinergic P2X(3) receptor, a major player in the transduction of sensory events in the bladder.

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.

Chloride regulation in the pain pathway.

Melzack and Wall's Gate Control Theory of Pain laid the theoretical groundwork for a role of spinal inhibition in endogenous pain control. While the Gate Control Theory was based on the notion that spinal inhibition is dynamically regulated, mechanisms underlying the regulation of inhibition have turned out to be far more complex than Melzack and Wall could have ever imagined. Recent evidence indicates that an exquisitely sensitive form of regulation involves changes in anion equilibrium potential (E(anion)), which subsequently impacts fast synaptic inhibition mediated by GABA(A), and to a lesser extent, glycine receptor activation, the prototypic ligand gated anion channels.

Visceral versus somatic pain: similarities and differences.

Inflammatory bowel disease and the irritable bowel syndrome are conditions characterized by chronic pain that generates persistent, hyperalgesic states in many regions of the body. It is difficult to explain the pain of conditions such as inflammatory bowel disease and irritable bowel syndrome by extrapolating directly from what is known about the mechanisms of somatic pain. Visceral and somatic pain show many differences not only in the psychophysics of the sensation, but also in the neurobiological mechanisms that mediate the sensory process.