Ultraviolet-B-induced mechanical hyperalgesia: A role for peripheral sensitisation
TL;DR: It is concluded that UVB‐induced mechanical hyperalgesia may be explained by a net shift in peripheral nociceptor response properties and alteration in mechanical responses of A&dgr;‐ and heat‐insensitive C‐nocicePTors were particular to stronger stimuli.
Abstract: Ultraviolet (UV) induced cutaneous inflammation is emerging as a model of pain with a novel sensory phenotype. A UVB dose of 1000mJ/cm2 produces a highly significant thermal and mechanical hypersensitivity. Here we examined the properties and mechanisms of such hyperalgesia in rats. Significantly, the mechanical hyperalgesia (with approximately 60% change in withdrawal thresholds) was restricted to the lesion site with no changes in mechanical threshold in adjacent non-irradiated skin (i.e. no secondary hypersensitivity), suggesting a peripheral mechanism. Consistent with this, we found that primary mechanical hypersensitivity showed no significant changes after intrathecal treatment with 10microg of the NMDA-receptor antagonist MK-801. Using an in vitro skin-nerve preparation, in the presence and absence of UVB-inflammation, suprathreshold responses to skin displacement stimuli of 6-768microm of 103 peripheral nociceptors were recorded. At the peak of UVB-induced hyperalgesia we observed that mechanical response properties of Adelta-nociceptors recorded from UVB-inflamed skin (n=19) were significantly diminished, by approximately 50%, compared to those recorded from naive skin (n=13). The mechanical response properties of heat-sensitive C-nociceptors were unchanged while their heat responses were significantly increased, by approximately 75%, in UVB-inflamed (n=26) compared to naive skin (n=12). Heat-insensitive C-nociceptors, however, demonstrated significantly enhanced (by approximately 60%) response properties to mechanical stimulation in UVB-inflamed (n=21) compared to naive skin (n=12). Notably alteration in mechanical responses of Adelta- and heat-insensitive C-nociceptors were particular to stronger stimuli. Spontaneous activity was not induced by this dose of UVB. We conclude that UVB-induced mechanical hyperalgesia may be explained by a net shift in peripheral nociceptor response properties.
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TL;DR: Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity.
Abstract: Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.
3,331 citations
Cites background from "Ultraviolet-B-induced mechanical hy..."
...the terminal was exposed to inflammatory modulators, the zone of primary hyperalgesia [23,41,138,146,178]....
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TL;DR: Given the poor efficacy of current analgesics, the selective expression of particular VGSCs in sensory neurons makes these attractive targets for drug discovery, and the increasing availability of gene sequencing and electrophysiological analysis of gene variants provides the opportunity to better target existing therapies in a personalized manner.
Abstract: Acute pain signaling has a key protective role and is highly evolutionarily conserved. Chronic pain, however, is maladaptive, occurring as a consequence of injury and disease, and is associated wit...
346 citations
TL;DR: It is indicated that C-Mechano Cold sensitive fibers exhibit enhanced firing to suprathreshold mechanical stimuli in a TRPA1-dependent manner during inflammation, and that input from these fibers drives mechanical hyperalgesia in inflamed mice.
Abstract: Inflammation is a part of the body’s natural response to tissue injury which initiates the healing process. Unfortunately, inflammation is frequently painful and leads to hypersensitivity to mechanical stimuli, which is difficult to treat clinically. While it is well established that altered sensory processing in the spinal cord contributes to mechanical hypersensitivity (central sensitization), it is still debated whether primary afferent neurons become sensitized to mechanical stimuli after tissue inflammation. We induced inflammation in C57BL/6 mice via intraplantar injection of Complete Freund’s Adjuvant. Cutaneous C fibers exhibited increased action potential firing to suprathreshold mechanical stimuli. We found that abnormal responses to intense mechanical stimuli were completely suppressed by acute incubation of the receptive terminals with the TRPA1 inhibitor, HC-030031. Further, elevated responses were predominantly exhibited by a specific subgroup of C fibers, which we determined to be C-Mechano Cold sensitive fibers. Thus, in the presence of HC-030031, C fiber mechanical responses in inflamed mice were not different than responses in saline-injected controls. We also demonstrate that injection of the HC-030031 compound into the hind paw of inflamed mice alleviates behavioral mechanical hyperalgesia without affecting heat hyperalgesia. Further, we pharmacologically anesthetized the TRPA1-expressing fibers in vivo by co-injecting the membrane-impermeable sodium channel inhibitor QX-314 and the TRPA1 agonist cinnamaldehyde into the hind paw. This approach also alleviated behavioral mechanical hyperalgesia in inflamed mice but left heat hypersensitivity intact. Our findings indicate that C-Mechano Cold sensitive fibers exhibit enhanced firing to suprathreshold mechanical stimuli in a TRPA1-dependent manner during inflammation, and that input from these fibers drives mechanical hyperalgesia in inflamed mice.
137 citations
Cites background from "Ultraviolet-B-induced mechanical hy..."
...Interestingly, a study of ultraviolet light-induced inflammation also reports elevated suprathreshold mechanical responses in heat-insensitive C fibers, which would include C-Mechano Cold fibers [34]....
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TL;DR: Viewing pain as a human experience that involved the synthesis of sensory, affective, and cognitive dimensions represented a momentous shift from unidimensional sensory models and underscored the distinction between pain and nociception.
Abstract: The experience of pain depends on interpretation of context and past experience that guide the choice of an immediate behavioral response and influence future decisions of actions to avoid harm. The aversive qualities of pain underlie its physiological role in learning and motivation. In this review, we highlight findings from human and animal investigations that suggest that both pain, and the relief of pain, are complex emotions that are comprised of feelings and their motivational consequences. Relief of aversive states, including pain, is rewarding. How relief of pain aversiveness occurs is not well understood. Termination of aversive states can directly provide relief as well as reinforce behaviors that result in avoidance of pain. Emerging preclinical data also suggests that relief may elicit a positive hedonic value that results from activation of neural cortical and mesolimbic brain circuits that may also motivate behavior. Brain circuits mediating the reward of pain relief, as well as relief-induced motivation are significantly impacted as pain becomes chronic. In chronic pain states, the negative motivational value of nociception may be increased while the value of the reward of pain relief may decrease. As a consequence, the impact of pain on these ancient, and conserved brain limbic circuits suggest a path forward for discovery of new pain therapies.
118 citations
Cites background from "Ultraviolet-B-induced mechanical hy..."
...This can be seen, for example, in lightly sunburned skin in which a normally innocuous heat stimulus is felt as burning pain.(16,69) Most clinically relevant pains have a tonic component...
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TL;DR: A clear correlation of the UVB response in rat and in human skin was shown, giving the authors confidence that their rat results would apply in humans, as well as proof that a neutralizing antibody to the chemokine protected against the pain and infiltration of immune cells.
Abstract: Many persistent pain states (pain lasting for hours, days, or longer) are poorly treated because of the limitations of existing therapies. Analgesics such as nonsteroidal anti-inflammatory drugs and opioids often provide incomplete pain relief and prolonged use results in the development of severe side effects. Identification of the key mediators of various types of pain could improve such therapies. Here, we tested the hypothesis that hitherto unrecognized cytokines and chemokines might act as mediators in inflammatory pain. We used ultraviolet B (UVB) irradiation to induce persistent, abnormal sensitivity to pain in humans and rats. The expression of more than 90 different inflammatory mediators was measured in treated skin at the peak of UVB-induced hypersensitivity with custom-made polymerase chain reaction arrays. There was a significant positive correlation in the overall expression profiles between the two species. The expression of several genes [interleukin-1β (IL-1β), IL-6, and cyclooxygenase-2 (COX-2)], previously shown to contribute to pain hypersensitivity, was significantly increased after UVB exposure, and there was dysregulation of several chemokines (CCL2, CCL3, CCL4, CCL7, CCL11, CXCL1, CXCL2, CXCL4, CXCL7, and CXCL8). Among the genes measured, CXCL5 was induced to the greatest extent by UVB treatment in human skin; when injected into the skin of rats, CXCL5 recapitulated the mechanical hypersensitivity caused by UVB irradiation. This hypersensitivity was associated with the infiltration of neutrophils and macrophages into the dermis, and neutralizing the effects of CXCL5 attenuated the abnormal pain-like behavior. Our findings demonstrate that the chemokine CXCL5 is a peripheral mediator of UVB-induced inflammatory pain, likely in humans as well as rats.
100 citations
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TL;DR: The Committee for Research and Ethical Issues of the International Association for the Study of Pain (IASP®) is concerned with the ethical aspects of studies producing experimental pain and any suffering it may cause in animals.
Abstract: The Committee for Research and Ethical Issues of the International Association for the Study of Pain (IASP®) is concerned with the ethical aspects of studies producing experimental pain and any suffering it may cause in animals. Such studies are essential if new and clinically relevant knowledge about the mechanisms of pain is to be acquired. Investigations in conscious animals intended to stimulate chronic pain in man are being performed. Such experiments require careful planning to avoid or at least minimize pain in the animals.
7,443 citations
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...The guidelines of the Committee for Research and Ethical Issues of the IASP [70] were followed....
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TL;DR: Both the thermal method and the Randall‐Selitto mechanical method detected dose‐related hyperalgesia and its blockade by either morphine or indomethacin, but the Thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
Abstract: A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
4,829 citations
Journal Article•
4,241 citations
TL;DR: Results indicate that NMDA receptors are involved in the induction and maintenance of the central sensitization produced by high threshold primary afferent inputs and have a bearing both on the potential role of NMDA antagonists for pre‐emptive analgesia and for treating established pain states.
Abstract: Repetitive stimulation of small diameter primary afferent fibres produces a progressive increase in action potential discharge (windup) and a prolonged increase in the excitability of neurones in the spinal cord following the stimulus. Previous studies have demonstrated that windup is the consequence of the temporal summation of slow synaptic potentials and that the slow potentials and windup are reduced by pretreatment with N-methyl-D-aspartic acid (NMDA) antagonists. We have now examined whether primary afferent induced hypersensitivity states in flexor motoneurones are also dependent on the activation of NMDA receptors and whether windup is a possible trigger for the production of the central hypersensitivity. Both a non-competitive (MK-801) and a competitive (D-CPP) NMDA antagonist, at doses that did not modify the baseline reflex, reduced the facilitation of the flexor reflex produced by either brief electrical stimulation of the sural nerve (1 Hz for 20 sec at C-fibre strength), or by the cutaneous application of the chemical irritant mustard oil. These antagonists also prevented windup from occurring in the motoneurones. When the the MK-801 and the D-CPP were administered once a state of central facilitation had been induced by prior treatment with mustard oil, they returned the facilitated reflex to its pretreatment level. These results indicate that NMDA receptors are involved in the induction and maintenance of the central sensitization produced by high threshold primary afferent inputs. Because central sensitization is likely to contribute to the post-injury pain hypersensitivity states in man, these data have a bearing both on the potential role of NMDA antagonists for pre-emptive analgesia and for treating established pain states.
1,903 citations
1,850 citations