Photophobia and allodynia in persistent post-traumatic headache are associated with higher disease burden.

OBJECTIVE: To assess photophobia and allodynia in subjects with post-traumatic headache and examine how these sensory hypersensitivities associate with clinical measures of disease burden. BACKGROUND: Post-traumatic headache is the most frequent and disabling long-term consequence of mild traumatic brain injury. There is evidence of sensory dysfunction in acute post-traumatic headache, and it is known from other headache conditions that sensory amplifications correlate with more severe disease. However, systematic studies in post-traumatic headache are surprisingly scarce. METHODS: We tested light and tactile sensitivity, along with measures of disease burden, in 30 persistent post-traumatic headache subjects and 35 controls. RESULTS: In all, 79% of post-traumatic headache subjects exhibited sensory hypersensitivity based on psychophysical assessment. Of those exhibiting hypersensitivity, 54% exhibited both light and tactile sensitivity. Finally, sensory thresholds were correlated across modalities, as well as with headache attack frequency. CONCLUSIONS: In this study, post-traumatic headache subjects with both light and tactile sensitivity had significantly higher headache frequencies and lower sensitivity thresholds to both modalities, compared to those with single or no sensory hypersensitivity. This pattern suggests that hypersensitivity across multiple modalities may be functionally synergistic, reflect a higher disease burden, and may serve as candidate markers of disease.

Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia.

Value information about a drug, such as the price tag, can strongly affect its therapeutic effect. We discovered that value information influences adverse treatment outcomes in humans even in the absence of an active substance. Labeling an inert treatment as expensive medication led to stronger nocebo hyperalgesia than labeling it as cheap medication. This effect was mediated by neural interactions between cortex, brainstem, and spinal cord. In particular, activity in the prefrontal cortex mediated the effect of value on nocebo hyperalgesia. Value furthermore modulated coupling between prefrontal areas, brainstem, and spinal cord, which might represent a flexible mechanism through which higher-cognitive representations, such as value, can modulate early pain processing.

Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy.

Relapsing-remitting multiple sclerosis is commonly associated with motor impairments, neuropathic pain, fatigue, mood disorders, and decreased life expectancy. However, preclinical pharmacological studies predominantly rely on clinical scoring of motor deficit as the sole behavioral endpoint. Thus, the translational potential of these studies is limited. Here, we have assessed the therapeutic potential of a novel anti-inflammatory interleukin-10 (IL-10) non-viral gene therapy formulation (XT-101-R) in a rat relapsing remitting experimental autoimmune encephalomyelitis (EAE) model. EAE induced motor deficits and neuropathic pain as reflected by induction of low-threshold mechanical allodynia, suppressed voluntary wheel running, decreased social exploration, and was associated with markedly enhanced mortality. We also noted that voluntary wheel running was depressed prior to the onset of motor deficit, and may therefore serve as a predictor of clinical symptoms onset. XT-101-R was intrathecally dosed only once at the onset of motor deficits, and attenuated each of the EAE-induced symptoms and improved survival, relative to vehicle control. This is the first pharmacological assessment of such a broad range of EAE symptoms, and provides support for IL-10 gene therapy as a clinical strategy for the treatment of multiple sclerosis.

Behavioral profile assessment in offspring of Swiss mice treated during pregnancy and lactation with caffeine.

The association between caffeine consumption and various psychiatric manifestations has long been observed. The objective was to assess the behavioral profile in offspring of Swiss mice treated during pregnancy and lactation with caffeine. For this purpose, two groups (n = 6 each and BW ~ 35 g) of female mice were treated during pregnancy and lactation by: tap water and caffeine solution at a concentration of 0.3 mg/mL through oral route. The offspring obtained, by completing 70 days of life, was underwent a behavioral battery test. Statistical analysis was performed by student t test and the different significance adopted was p < 0.05. According to our results, it was not found any significant differences in tail suspension and forced swimming tests. In anxiety related responses however, the mice of caffeine group had greater number of fecal pellets (178 %, p = 0.001) in the open field test, higher number of attempts (51 %, p = 0.03) in light-dark box and decreased percentage of entries in open arms (41 %, p = 0.01) in elevated plus maze test. Moreover, in the marble burying test, there was a significant decrease in the number of buried marbles compared with controls (110 %, p = 0,002). In the meantime, in the von Frey test, it was observed an exacerbation of mechanical allodynia both in basal conditions and after the carrageenan administration (p < 0.001). Furthermore, caffeine treatment during pregnancy and lactation causes long-term behavioral changes in the mice offspring that manifest later in life.

Mechanical Conflict System: A Novel Operant Method for the Assessment of Nociceptive Behavior.

A new operant test for preclinical pain research, termed the Mechanical Conflict System (MCS), is presented. Rats were given a choice either to remain in a brightly lit compartment or to escape to a dark compartment by crossing an array of height-adjustable nociceptive probes. Latency to escape the light compartment was evaluated with varying probe heights (0, .5, 1, 2, 3, and 4 mm above compartment floor) in rats with neuropathic pain induced by constriction nerve injury (CCI) and in naive control rats. Escape responses in CCI rats were assessed following intraperitoneal administration of pregabalin (10 and 30 mg/kg), morphine (2.5 and 5 mg/kg), and the tachykinin NK1 receptor antagonist, RP 67580 (1 and 10 mg/kg). Results indicate that escape latency increased as a function of probe height in both naive and CCI rats. Pregabalin (10 and 30 mg/kg) and morphine (5 mg/kg), but not RP 67580, decreased latency to escape in CCI rats suggesting an antinociceptive effect. In contrast, morphine (10 mg/kg) but not pregabalin (30 mg/kg) increased escape latency in naive rats suggesting a possible anxiolytic action of morphine in response to light-induced fear. No order effects following multiple test sessions were observed. We conclude that the MCS is a valid method to assess behavioral signs of affective pain in rodents.

Development of a bedside pain assessment kit for the classification of patients with osteoarthritis.

There are no standardized bedside assessments for subtyping patients with osteoarthritis (OA) based on pain mechanisms. Thus, we developed a bedside sensory testing kit (BSTK) to classify OA patients based on sensory profiles potentially indicative of pain mechanism. After usability and informal reliability testing (n = 22), the kit was tested in a formal reliability study (n = 20). Patients completed questionnaires and sensory testing: pressure algometry to detect hyperalgesia; repeat algometry after heterotopic noxious conditioning stimulation to measure diffuse noxious inhibitory control (DNIC); light touch using Von Frey filaments; and cold allodynia using a brass rod. The procedure was brief and well tolerated. Algometry and filament testing were highly reliable [intra-class correlation coefficients (ICCs) 0.71-0.91]; DNIC was acceptably reliable (ICCs 0.53-0.91); brass rod reliability was inconclusive. Patients were classified empirically into four groups: "All abnormal findings" (primary and secondary hyperalgesia and dysfunctional DNIC); "all normal findings"; and two intermediate groups. The "all abnormal findings" group had more neuropathic pain symptoms, and lower WOMAC total, stiffness, and activity scores than the "all normal findings" group. Simple BSTK procedures, consolidated in a kit, reliably classified OA patients into subgroups based on sensory profile, suggesting that OA patients differ in underlying pain mechanisms. Further research is needed to confirm these subgroups and determine their validity in predicting response to treatment.

Assessment of avoidance behaviors in mouse models of muscle pain.

Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the cortex. Animal models typically use reflexive behaviors to test nociceptive responses; these are thought to reflect the sensory dimension of pain. While several behavioral tests are available for examining the affective dimension of pain it is unclear if these are appropriate in animal models of muscle pain. We therefore tested the utility of existing paradigms as well as new avoidance paradigms in animal models of muscle pain in mice. Specifically we used an escape-avoidance test to noxious mechanical stimuli, a learned avoidance test to noxious mechanical stimuli, and avoidance of physical activity. We used three animal models of muscle pain: carrageenan-induced inflammation, non-inflammatory muscle pain, and exercise-enhanced pain. In the carrageenan model of inflammation mice developed escape-avoidance behaviors to mechanical stimuli, learned avoidance to mechanical stimulation and avoidance of physical activity - these models are associated with unilateral hyperalgesia. When both muscles were inflamed, escape-avoidance behaviors did not develop suggesting that equivalent bilateral pain behaviors cannot be tested with an escape-avoidance test. In the non-inflammatory muscle pain model mice did not show significant changes in escape-avoidance behaviors or learned avoidance, but did avoid physical activity. In the exercise-enhanced pain model, there were no changes in escape-avoidance, learned avoidance of noxious or physical activity In conclusion, we developed several testing protocols that assess supraspinal processing of pain behaviors in models of muscle pain and that are most sensitive in animals with unilateral hyperalgesia.

The assessment of cold hyperalgesia after an incision.

BACKGROUND: Although cold hypersensitivity is a well-documented phenomenon in animals and humans with inflammatory and neuropathic pain, little is known about the presence of cold hyperalgesia after surgery. Therefore, we studied primary cold hyperalgesia after a surgical incision in mice. METHODS: Before and after plantar incision, inflammation with complete Freund adjuvant, and spared nerve ligation, unrestrained male animals were placed on a Peltier-cooled cold plate with a surface temperature of 0 degrees C and withdrawal latencies were measured. Additionally, incision-induced cold hyperalgesia was also assessed in female animals. Furthermore, skin temperature before and after plantar incision and inflammation were assessed by using infrared thermography (Varioscan LW 3011; Infratec, Dresden, Germany). RESULTS: Cold hyperalgesia to a noxious cold stimulus was observed after inflammation and nerve injury but not after a surgical incision. Similar results were demonstrated for female animals after incision. Furthermore, a significant increase in skin temperature was recorded after inflammation but not after incision, indicating that a surgery evokes only minor inflammatory effects. CONCLUSION: The present data give strong evidence that a surgical incision does not cause cold hyperalgesia. Furthermore, a lack of cold hyperalgesia in unrestrained male and female mice after incision was not due to increased skin temperature after incision. Finally, we demonstrated that in contrast to a surgical incision, inflammation and nerve injury generate intense cold hyperalgesia and an increase in skin temperature, suggesting that different mechanisms are involved in surgical and inflammatory or neuropathic pain.

Behavioral and immunohistological assessment of painful neuropathy induced by a single oxaliplatin injection in the rat.

In clinical use, a single infusion of oxaliplatin, widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs triggered or aggravated by exposure to cold. To study the pathophysiology of these symptoms, we developed and characterized an animal model that reproduces the effects of a single intraperitoneal oxaliplatin administration (3, 6 and 12 mg/kg). Significant allodynia and hyperalgesia to cold stimuli were rapidly observed from 24 h to day 5 with a maximum lowering of 76% at t+30 h versus control. Other behavioral assessments revealed rapid persistent mechanical allodynia, but no thermal hyperalgesia or allodynia to heat and no hyperalgesia to mechanical stimuli. An immunohistochemical study in the superficial layers of the spinal dorsal horn revealed a marked increase in substance P immunoreactivity versus controls (12% versus 4%), whereas calcitonin gene-related peptide (CGRP) immunoreactivity was unchanged. This new animal model for the first time closely mimics the effects observed in humans after a single oxaliplatin infusion, especially onset and highly intense sensory disturbances, hypersensitivity to cold with allodynia and hyperalgesia signs. This model may help to elucidate the mechanisms of this thermal hypersensitivity, especially the possible involvement of small-diameter A-fibers in cold allodynia symptoms. These selective effects may clue up the mechanistic basis for the acute oxaliplatin neuropathy leading to a better understanding of the clinical condition and to optimize its treatment.

A clinical laboratory model for direct assessment of medication-induced antihyperalgesia and subjective effects: initial validation study.

Analgesic medications are often tested in clinical laboratory studies by observing their ability to reduce the pain produced by noxious stimuli presented to healthy skin. These medications may then be used clinically to reduce disease-related hyperalgesia. This article describes a clinical laboratory model useful for testing a medication's ability to reduce hyperalgesia in humans. Results demonstrate that ultraviolet (UV) light induces hyperalgesia, commonly prescribed analgesic medications reduce UV-induced hyperalgesia, and this UV-induced hyperalgesia model can be used to assess the time course of a medication's antihyperalgesia effects. Coupled with participant-rated measures of drug liking and mood, this model may prove useful for predicting the clinical efficacy and side-effect profile of novel analgesic medications in cost-efficient and statistically powerful laboratory studies.