The impact of foot shock-induced stress on pain-related behavior associated with burn injury

Acute pain is prevalent following burn injury and can often transition to chronic pain. Prolonged acute pain is an important risk factor for chronic pain and there is little preclinical research to address this problem. Using a mouse model of second-degree burn, we investigated whether pre-existing stress influences pain(sensitivity) after a burn injury. We introduced a contribution of stress in two different ways: (1) the use of foot-shock as a pre-injury stressor or (2) the use of A/J mice to represent higher pre-existing stress compared to C57Bl/6 mice. C57Bl/6 and A/J mice were exposed to repeated mild foot shock to induce stress for 10 continuous days and mice underwent either burn injury or sham burn injury of the plantar surface of the right hind paw. Assessments of mechanical and thermal sensitivities of the injured and uninjured paw were conducted during the shock protocol and at intervals up to 82-day post-burn injury. In both strains of mice that underwent burn injury, thermal hypersensitivity and mechanical allodynia appeared rapidly in the ipsilateral paw. Mice that were stressed took much longer to recover their hind paw mechanical thresholds to baseline compared to non-stressed mice in both burn and non-burn groups. Analysis of the two mouse strains revealed that the recovery of mechanical thresholds in A/J mice which display higher levels of baseline anxiety was shorter than C57Bl/6 mice. No differences were observed regarding thermal sensitivities between strains. Our results support the view that stress exposure prior to burn injury affects mechanical and thermal thresholds and may be relevant to as a risk factor for the transition from acute to chronic pain. Finally, genetic differences may play a key role in modality-specific recovery following burn injury.     

Central Sensitization Theory of Migraine: Clinical Implications

The clinical science of migraine headache continues to evolve. Theories of the pathophysiology of migraine have progressed from the early vascular basis of migraine to more complex current theories that emphasize the centrality of neuronal dysfunction. The most recently articulated theory of migraine is the central sensitization hypothesis, which proposes that altered processing of sensory input in the brainstem, principally the trigeminal nucleus caudalis, could account for many of the temporal and symptomatic features of migraine, as well as its poor response to triptan therapy when such treatment is initiated hours after the onset of pain. Both preclinical and clinical data support the central sensitization theory. A critical clinical implication of this theory is that drugs that are capable of either aborting or arresting the process of central sensitization, most prominently dihydroergotamine, may have a unique role in the treatment of migraine. An additional, and highly practical, implication is based upon the finding that cutaneous allodynia—pain arising from innocuous stimulation of the skin, as in hair brushing or the application of cosmetics—is an easily identifiable marker of central sensitization. Thus, the presence or absence of cutaneous allodynia can be integrated into the routine clinical assessment of migraine and utilized as a determinant of treatment. Future basic and clinical research on central sensitization is likely to be of ongoing importance to the field.     

Lamotrigine in the treatment of painful diabetic neuropathy

An open trial was conducted to study the potential efficacy of lamotrigine, a novel antiepileptic agent that blocks voltage-sensitive sodium channels and inhibits the release of glutamate, in relieving the pain associated with diabetic neuropathy. Subsequent to a 1 week washout period from previous analgesics, lamotrigine was administered at a dose of 25 mg/day for 1 week. The dose was doubled on a weekly basis up to 400 mg/day over 6 weeks. The McGill pain questionnaire (MPQ), spontaneous pain and a series of mechanical and thermal stimuli-induced pain were measured with the use of 0–100 visual analogue scale (VAS), on seven office visits. Pain level was also recorded by each patient twice daily, 1 week before, during, and 2 weeks after the treatment period with the use of a 0–10 numerical pain scale (NPS). Quantitative mechanical (Von Frey filaments) and thermal testing (QTT), and routine blood tests were performed at the beginning and at the end of the study. Thirteen patients completed the study. Spontaneous pain measured by VAS and NPS gradually dropped from a baseline of 49 ± 8 and 6.8 ± 0.6, to 20 ± 8.6 ( p < 0.001) and 4.3 ± 0.9 ( p < 0.001), respectively, at the end of the treatment period. Similarly, cold allodynia dropped from 38 ± 9.2 to 16 ± 15.3 ( p = 0.01), and the MPQ score from 13.6 ± 0.8 to 11.0 ± 1.5 ( p < 0.01). In contrast, no significant changes were found in the QTT, mechanical pain thresholds and laboratory results. Two patients were withdrawn from the study because of adverse effects. A long-term follow up showed that most patients were still using lamotrigine 6 months after the end of the study. The results of the study suggest that lamotrigine is potentially effective and safe in treating painful diabetic neuropathy.     

Comparison of three models of neuropathic pain in mice using a new method to assess cold allodynia: The double plate technique

The recent identification of receptors sensitive to cold stimuli increased the significance of using mice to study cold allodynia, one of the important features of neuropathic pain. However, commonly used techniques (simple cold plate and acetone technique) may be inappropriate to study cold allodynia in mice because of problems of interpretation. We have developed a new method for assessing aversion to a cold non-noxious stimulus. It consists of calculating the time that mice spend on a non-noxious cold plate during their explorative behavior versus a thermoneutral one. We used three different models of neuropathic pain: chronic constriction injury of the sciatic nerve (CCI), partial sciatic nerve ligation (PSL) and chronic constriction of the saphenous nerve (CCS) with their respective sham groups and naive animals to assess the double plate in comparison to the acetone drop technique. All operated mice displayed cold allodynia with both methods. The response to acetone and the time spent on the cold plate were correlated (r = −0.93) and we also showed that the CCI mice were more sensitive to cold. Pharmacological validation of this technique showed that CCI induced cold allodynia was alleviated by gabapentin. In conclusion, the double plate technique provides a new, relevant method for assessing cold allodynia in mice. The advantages and drawbacks with the other techniques are discussed.     

己酮可可碱对选择性坐骨神经分支损伤大鼠脊髓星形胶质细胞的影响

目的观察己酮可可碱腹腔注射对选择性坐骨神经分支损伤大鼠(SNI)脊髓星形胶质细胞的影响。方法切断腓总神经和胫神经保留腓肠神经,制作坐骨神经分支选择性损伤模型。雄性SD大鼠48只随机分为:假手术组(Sh)、模型组(SNI)、己酮可可碱组(PTX)。PTX组从术前1d起至术后6d连续7d,每日一次腹腔注射己酮可可碱100mg/kg。观察指标包括:术前1d,术后1、3、5、7、14d的机械缩足反射阈值(MWT)和热缩足反射持续时间(TWD);不同组别脊髓星形胶质细胞标志物GFAP在术后1d、3d、7d、14d的表达。结果大鼠坐骨神经选择性切断后1d起MWT降低,TWD延长,与假手术组比差异显著(p<0.05);己酮可可碱腹腔注射抑制MWT降低和TWD延长,与模型组相比差异显著(p<0.05);己酮可可碱腹腔注射可减少部分坐骨神经切断后脊髓GFAP的表达,减少星形胶质细胞阳性细胞数。结论己酮可可碱腹腔注射可抑制SNI脊髓星形胶质细胞的增生,减轻痛觉超敏和痛觉过敏。     

Mechanisms of Pefloxacin-Induced Pain

In electrophysiological and behavioral experiments on rats we studied the effects of pefloxacin, a member of fluoroquinolone family, on the nociceptive system. Intraperitoneal injection of pefloxacin (80 mg/kg) decreased the thresholds of nociceptive response to noxious stimulation in the hot-plate test. In addition, it decreased the threshold of the late component of nociceptive flexor reflex. Intrathecal application of pefloxacin in a dose of 20 microg provoked allodynia, while the higher dose of 400 microg induced behavioral pattern characteristic of central pain syndrome. It was hypothesized that pain induced by pefloxacin results from disturbances in GABAergic inhibition in the central subdivisions of the nociceptive system.     

Behavioral characteristics of a mouse model of cancer pain

Pain is a major symptom in cancer patients, and most cancer patients with advanced or terminal cancers suffer from chronic pain related to treatment failure and/or tumor progression. In the present study, we examined the development of cancer pain in mice. Murine hepatocarcinoma cells, HCa-1, were inoculated unilaterally into the thigh or the dorsum of the foot of male C3H/HeJ mice. Four weeks after inoculation, behavioral signs were observed for mechanical allodynia, cold allodynia, and hyperalgesia using a von Frey filament, acetone, and radiant heat, respectively. Bone invasion by the tumor commenced from 7 days after inoculation of tumor cells and was evident from 14 days after inoculation. Cold allodynia but neither mechanical allodynia nor hyperalgesia was observed in mice that received an inoculation into the thigh. On the contrary, mechanical allodynia and cold allodynia, but not hyperalgesia, were developed in mice with an inoculation into the foot. Sometimes, mirror-image pain was developed in these animals. These results suggest that carcinoma cells injected into the foot of mice may develop severe chronic pain related to cancer. This animal model of pain would be useful to elucidate the mechanisms of cancer pain in humans.     

Inhibition of nociceptin-induced allodynia in conscious mice by prostaglandin D2

1. We recently showed that intrathecal administration of nociceptin induced allodynia by innocuous tactile stimuli and hyperalgesia by noxious thermal stimuli in conscious mice. In the present study, we examined the effect of prostaglandins on nociceptin-induced allodynia and hyperalgesia.
2. Prostaglandin D₂ (PGD₂) blocked the allodynia induced by nociceptin in a dose-dependent manner with an IC₅₀ of 26 ng kg⁻¹, but did not affect the nociceptin-induced hyperalgesia at doses up to 500 ng kg⁻¹. BW 245C (an agonist for PGD (DP) receptor) blocked the allodynia with an IC₅₀ of 83 ng kg⁻¹.
3. The blockade of nociceptin-induced allodynia by PGD₂ was reversed by the potent and selective DP-receptor antagonist BW A868C in a dose-dependent manner with an ED₅₀ of 42.8 ng kg⁻¹.
4. Glycine (500 ng kg⁻¹) almost completely blocked the nociceptin-induced allodynia. A synergistic effect on the inhibition of nociceptin-evoked allodynia was observed between glycine and PGD₂ at below effective doses.
5. Dibutyryl cyclic AMP, but not dibutyryl cyclic GMP, blocked the nociceptin-induced allodynia with an IC₅₀ of 2.9 μg kg⁻¹.
6. PGE₂, PGF_2α, butaprost (an EP₂ agonist) and cicaprost (a PGI receptor agonist) did not affect the nociceptin-induced allodynia.
7. These results demonstrate that PGD₂ inhibits the nociceptin-evoked allodynia through DP receptors in the spinal cord and that glycine may be involved in this inhibition.

     

Marked enhancement of anti-allodynic effect by combined intrathecal administration of the adenosine A1-receptor agonist R-phenylisopropyladenosine and morphine in a rat model of central pain

BACKGROUND: There is often no satisfactory treatment for chronic pain after spinal cord injury. We have previously reported that intrathecal (i.t.) administration of the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) or the opioid morphine has anti-allodynic effects in a model of presumed chronic central pain after photochemically induced spinal cord injury in rats. In the present study, we set out to investigate the possible interaction between i.t. R-PIA and morphine in spinally injured rats. METHODS: Sprague-Dawley rats displaying allodynia-like behaviors to mechanical and cold stimuli after photochemically induced spinal cord injury with minor motor deficits were used. R-PIA and morphine, either alone or in combination, were administered i.t. through an implanted catheter to lumbar spinal cord. RESULTS: Cumulative doses of R-PIA or morphine dose-dependently reduced the mechanical allodynia-like behavior, with a threshold of 1 nmol and 1.5 nmol, respectively. When co-administrated, R-PIA and morphine produced marked suppression of mechanical allodynia at doses of 5 pmol and 7.5 pmol, respectively. The effect of i.t. co-administration of R-PIA and morphine on cold allodynia was comparable to i.t. R-PIA alone. The combination of R-PIA and morphine did not increase adverse effects such as motor deficits in comparison to either drug alone. CONCLUSION: These results demonstrate a supra-additive interaction between the adenosine A1-receptor agonist R-PIA and morphine to reduce mechanical allodynia-like behavior in rats with chronic spinal cord injury. The combination of R-PIA and morphine administered spinally may be superior to R-PIA or morphine alone for treating such pain.     

Psychological profiles among women with vulvar vestibulitis syndrome: a chart review

The purpose of this study was to assess the prevalence and type of psychological distress in women with vulvar vestibulitis syndrome (VVS), A retrospective chart review was conducted of all women receiving a diagnosis of VVS referred to a tertiary care facility during a two-year period. Brief psychological questionnaires, including the Personality Assessment Screener, Fear of Negative Evaluation Scale, Golombok-Rust Inventory of Sexual Satisfaction, and the Phobia Rating Scale were administered.

Fifty-consecutive cases were reviewed along with 12-15 month follow-up data for 41 cases. Phobic anxiety to vaginal touch or entry was significantly higher in women with VVS than normative data. Fear of Negative Evaluation was a strong associated feature, and for 30% approached clinically significant levels. Twenty-six percent showed a moderate, while another 26% showed a mild clinically distressed profile. Negative affect and social withdrawal were among the most frequently endorsed variables. Improvement in allodynia and intercourse were both related to these psychological variables, and a multiple regression analysis supported the use of psychological instruments in addition to standard medical assessment.

A subgroup of women with VVS display clinically significant broad based psychological distress that warrants additional assessment. The use of psychological questionnaires in addition to medical assessment of women with VVS may provide valuable information predictive of treatment needs and response.