Presence Of Hyperalgesia Research Articles

Bone Turnover Markers and Wnt Signaling Modulators in Early Complex Regional Pain Syndrome. A Pre-specified Observational Study.

To explore serum levels of some bone turnover markers and the involvement of the Wnt signaling in CRPS-1. Query ID="Q1" Text="Please check and confirm whether the edit made to the article title is in order." We conducted an observational study on patients with early CRPS-1 recruited before any treatment. Clinical measures were assessed together with biochemical evaluation. Values of sclerostin, DKK1, CTX-I, and P1NP were compared with sex-age-matched healthy controls (HCs). We enrolled 34 patients diagnosed with CRPS-1 (mean age 59.3 ± 10.6years, Male/Female 10/24), median disease duration = 2weeks (IQR 1-5); median VAS score = 76 (IQR 68-80). Foot localization was slightly more frequent than hand localization (18/16). No statistically significant difference was found between CRPS-1 patients and HCs for CTX-I (0.3 ± 0.1ng/ml vs 0.3 ± 0.1, p = 0.140), while mean serum values of P1NP were significantly higher in CRPS-1 patients compared to HCs (70.0 ± 38.8ng/ml vs 50.1 ± 13.6, p = 0.005). Mean levels of sclerostin and DKK1 were lower in CRPS-1 patients vs HCs (sclerostin 28.4 ± 10.8pmol/l vs 34.1 ± 11.6, p = 0.004; DKK1 12.9 ± 10.8pmol/l vs 24.1 ± 11.9, p = 0.001). No statistically significant difference was found for all biochemical assessments in a subgroup of fracture-induced CRPS-1. No statistically significant differences were observed according to disease localization, disease duration, presence of hyperalgesia, allodynia, sudomotor alterations, and mild or moderate/severe swelling. No significant correlation emerged between sclerostin, DKK1 levels, baseline VAS score, or McGill Pain Questionnaire score. Bone involvement in early CRPS-1 does not seem to rely on increased osteoclast activity. Conversely, a serum marker of bone formation resulted increased. Both Sclerostin and DKK1 showed decreased values, probably suggesting a widespread osteocyte loss of function.Trial registration number: Eudract Number: 2014-001156-28.

24-LB: Guanfacine Normalizes Presynaptic Alpha-2 Adrenoceptors Enrichment and Ameliorates Neuropathic Pain in Type 1 Diabetic Rats

Diabetes is associated with several complications, including neuropathic pain, which is challenging to manage with currently available drugs. Descending noradrenergic neurons possess anti-nociceptive activity; however their involvement in diabetic neuropathic pain remains to be explored. To infer the regulatory role of this system, we examined in the pons, a part of the brainstem, lumbar nerves of the spinal cord and dorsal root ganglia of streptozotocin (STZ) -treated rats, a model for type 1 diabetes (T1D) , the localization (immunofluorescence) and the mRNA (qRT-PCR) and protein (Western blotting) expression of alpha-2A adrenoceptor (ADRA2A) . The data revealed that presynaptic SNAP-25 labeled ADRA2A in the central and peripheral nervous system of STZ diabetic rats were up-regulated both at the mRNA and protein levels. Interestingly, the levels of PSD-95 labeled postsynaptic neuronal ADRA2A remain unaltered as a function of diabetes. These biochemical abnormalities in the noradrenergic system of diabetic animals were associated with increased pain sensitivity as typified by the presence of hyperalgesia and cold/mechanical allodynia. The latter pain-related behaviors were assessed using Hargreaves apparatus, cold-plate and dynamic plantar aesthesiometer. Chronically administered guanfacine, a selective ADRA2A agonist, to diabetic animals downregulated the upregulation of neuronal presynaptic ADRA2A and ameliorated the hyperalgesia and the cold/mechanical allodynia in these animals. Together, these findings demonstrate that guanfacine may function as a potent analgesic and highlight ADRA2A, a key component of the descending neuronal autoinhibitory pathway as a potential therapeutic target in the treatment of diabetic neuropathic pain. Disclosure N. Munawar: None. A. Al madhoun: None. J. Nader: None. W. Al-ali: None. W. Masocha: None. F. Al-mulla: None. M. S. Bitar: None. Funding Grant YM05/19 from Kuwait University Research Sector.

Sigma-1 receptor antagonist (BD-1063) potentiates the antinociceptive effect of quercetin in neuropathic pain induced by chronic constriction injury.

Neuropathic pain is characterized by the presence of hyperalgesia and allodynia. Pharmacological treatments include the use of antiepileptics such as pregabalin or gabapentin, as well as antidepressants; however, given the role of the sigma-1 receptor in the generation and maintenance of pain, it has been suggested that sigma-1 receptor antagonists may be effective. There are also other alternatives that have been explored, such as the use of flavonoids such as quercetin. Due to the relevance of drug combinations in therapeutics, the objective of this work was to evaluate the effect of the combination of BD-1063 with quercetin in a chronic sciatic nerve constriction model using the "Surface of Synergistic Interaction" analysis method. The combination had preferable additive or synergistic effects, with BD-1063 (17.8 mg/kg) + QUER (5.6 mg/kg) showing the best antinociceptive effects. The required doses were also lower than those used individually to obtain the same level of effect. Our results provide the first evidence that the combination of a sigma-1 receptor antagonist and the flavonoid quercetin may be useful in the treatment of nociceptive behaviors associated with neuropathic pain, suggesting a new therapeutic alternative for this type of pain.

Chronic Exposure to Morphine Leads to a Reduced Affective Pain Response in the Presence of Hyperalgesia in an Animal Model of Empathy.

BackgroundEmpathy is the capability to represent the mental and emotional states of other subjects. Previous studies have demonstrated a possible correlation between morphine addiction and altered empathy response in morphine-addicted subjects. This study was performed to evaluate the effect of chronic morphine exposure as an animal model of morphine addiction on empathic changes in affective and sensory pain.MethodsAdult male Wistar rats (3 months old) were used for the current study. Animals were grouped in cages of two (n = 8 for each group) and one animal was selected as the pain observer group. Pain observer animals received either saline or morphine (10 mg/kg, twice daily for 8 days). At ninth day, formalin [50 µg, 5%, subcutaneous (SC)] was injected into the hindpaw of the cagemate and placed inside the cage. Elevated plus maze (EPM) and open field test (OFT) were recruited to evaluate anxiety; hot plate and tail flick tests were used to assay sensory pain. Conditioned place aversion (CPA) was also measured as indicator of affective pain component.FindingsChronic morphine exposure led to a reduced level of anxiety in EPM and OFT assays. An opioid-induced hyperalgesia was observed in the sensory pain assays, while there was a reduced affective pain in the CPA paradigm in morphine-treated animals.ConclusionIt might be plausible that chronic morphine exposure might alter empathy for pain through affective and not sensory pain pathways.

Features of research of reflected pains in patients with multiple sclerosis

Reflected pain (RP) is a variant of pain irradiation. In the case of pathology of internal organs, pain can spread to zones of certain dermatomes (viscero-sensory phenomenon), which are known as Zakharyin–Ged zones.The objective: to analyze the data of the study of the PR – Zakharin–Ged zones, carried out with the help of the Ged test in patients with multiple sclerosis (MS).Materials and methods. It was investigated in 216 patients with MS, using the classical H. Head sample, that in patients with MS, PR occur both from hypoesthesia zones and from areas of hyperesthesia, and in the arrangement of such zones is a definite system: they are associated with Zakharyin1Ged zones, where the PR is localized in pathology of internal organs.Results. The study of the Zakharyin–Ged zones revealed the presence of pain and the appearance of distant visceral pain sensations in 159 (73,6%) patients with MS of the general sample.Conclusions. The presence of hyperalgesia in the zones of Zakharyin–Ged and trigger points and also PR is systemic in nature and can provoke or intensify some neurological or somatic symptoms in MS patients.

Painful temporomandibular disorders and central sensitization: implications for management—a pilot study

The objective was to investigate the presence of cutaneous allodynia and hyperalgesia in the trigeminal and extra-trigeminal areas, as a surrogate for central sensitization (CS), in women with a painful temporomandibular disorder (TMD) and without other painful conditions. Painful TMDs, depression, and non-specific physical symptoms (NSPS) were classified according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). The amount of pain in the trigeminal and extra-trigeminal areas was determined using a visual analogue scale (0–100mm) after the application of a vibrotactile stimulus and assessment of the pressure pain threshold (PPT). Statistical tests (Fisher's, χ2, and Mann–Whitney) were performed, with a significance level of 5%. The sample comprised 45 women (mean age 37.5 years; 16 with a painful TMD) who were free of any headache, fibromyalgia, or other painful condition. Painful TMD was associated with higher pain sensitivity and lower PPT values in the trigeminal (P<0.01) and extra-trigeminal regions (P<0.01). The presence of depression contributed significantly to increased pain sensitivity. The presence of hyperalgesia and allodynia in both the trigeminal and extra-trigeminal regions among women with a painful TMD indicated the presence of CS. Changes involving the central nervous system should be considered during the evaluation and management of patients with a painful TMD.

Assessment of incising ethology in the absence and presence of jaw muscle hyperalgesia in a mouse home cage environment

IntroductionAssessment of oral motor behavior in a mouse is challenging due to the lack of currently available techniques that are non-invasive and allow long-term assessment in a home cage environment. The purpose of this study was to evaluate incising behavior using mouse chow attached to a three-dimensional force transducer that was mounted on the existing home cage. In addition, a persistent hyperalgesia condition was introduced to evaluate the sensitivity of the technique to identify incising behavioral changes. MethodsIncising activity of CD-1 male and female mice (n=48) was evaluated over a 24hour recording session during four baseline and six longitudinal hyperalgesia assessment sessions using custom written software. A pre-clinical persistent pain model was used to induce hyperalgesia in the masseter muscle by repetitive acidic saline injections. Sex and age differences were evaluated for multiple incising variables during both light and dark cycles during baseline and hyperalgesia conditions. ResultsSignificant sex differences were found for multiple incising variables but not for age. Discrete incising frequencies were identified in the range of 4.6–10.4Hz and were reproducibly found in both female and male mice. A significant shift to lower incising frequencies was observed after repetitive acidic saline injections compared to neutral saline injections. This shift to lower frequencies of incising returned to baseline levels after approximately four weeks but was statistically longer in female compared to male mice. Significant differences were also found for chow intake (reduced) and weight change during the hyperalgesia condition. No significant differences were found for total number of incisions or number of incising episodes per day or incising force. ConclusionsThe findings from this study support the use of recording three dimensional incising forces as a sensitive measure of incising behavior. This novel technique allowed the identification of specific incising variables that were differentially affected in female and male mice during a persistent hyperalgesia. The data were collected in the home cage environment with minimal bias such as experimenter interaction. Similar to other dental pain studies, mice were able to maintain normal incising activity levels per day (total incisions, total number of incising episodes) even in the presence of hyperalgesia.

A pain model with a neuropathic somatosensory lesion: Morton neuroma

A randomized, double-blind, three-period cross-over study was performed to characterize the sensory phenotype and pain demographics in patients with Morton neuroma (n=27) and to explore the effects of local administration (2mL) of placebo and lidocaine (1 and 10mg/mL) around the neuroma. Using the pain quality assessment scale (PQAS), the highest rating was seen for unpleasant pain and intensity of deep pain and the lowest for sensitive skin. Ongoing pain was reported in 32% of patients. Patients reported mild to moderate average pain, and that pain had interfered with sleep only marginally. Quantitative sensory testing (QST) measurements in the innervation territory showed hypophenomena or hyperphenomena in all patients, indicating that all had neuropathy. There was no particular QST modality that appeared to be specifically affected. Even the high-dose lidocaine resulted in limited effects on nerve-impulse conduction as judged by the effect on QST variables. However, both doses of lidocaine significantly reduced pain after step-ups, compared to placebo, indicating that lidocaine in this setting affected predominantly impulse generation and not impulse conduction. Following placebo treatment, pain after step-ups was similar in patients with and without hyperalgesia, indicating that the presence of hyperalgesia does not affect the pain intensity evoked by step-ups or walking.This pain model in patients with Morton neuroma allows investigation of drugs in a cross-over design and provides an opportunity to explore drug effects on both pain and QST variables. Commonly, neuromas are surgically removed and can be characterized in depth in vitro, thereby allowing close links to be established between pathophysiology and drug effect.

Peripheral antinociceptive effect of anandamide and drugs that affect the endocannabinoid system on the formalin test in normal and streptozotocin-diabetic rats

Diabetes is often associated with painful neuropathy. The current treatments are symptomatic and ineffective. Cannabinoids have been proposed as promising drugs for chronic pain treatment and its antinociceptive effect has already been related in nerve injury models of neuropathic pain, but little has been investigated in painful diabetic neuropathy models. Thus, the current study aims to investigate the potential antinociceptive effect of drugs that alter endocannabinoid system when injected subcutaneously into the dorsal surface of the ipsilateral hind paw in chemical hyperalgesia induced by formalin in both normoglycemic (Ngl) and streptozotocin-diabetic (Dbt) rats. Diabetic rats exhibited exaggerated flinching behaviors during first and second phases of the formalin test, indicating the presence of hyperalgesia. AM404, an anandamide (AEA) re-uptake inhibitor, AEA (an agonist of CB1/CB2 receptors) or ACEA (a selective CB1 receptor agonist) induced antinociception in both phases of formalin test in Ngl and Dbt rats. In both groups, the antinociceptive effect of ACEA was prevented by AM251, a CB1 inverse agonist while the antinociceptive effect of AEA was prevented by AM251 or AM630, a CB2 receptor antagonist. In Ngl rats, the antinociceptive effect of AM404 was prevented by AM251 or capsazepine only during first phase of the formalin test while in Dbt rats, this effect was blocked by pretreatment with AM251 (both phases) or AM630 (second phase). Taken together, these results demonstrated broad-spectrum antinociceptive properties of cannabinoids in a model of painful diabetic neuropathy. Peripheral activation of both cannabinoid receptors seems to mediate the antinociceptive effect of exogenous or endogenous anandamide.

Early thermal quantitative sensory testing to measure acute oxaliplatin neurotoxicity and predict chronic neuropathy in gastrointestinal malignancies.

425 Background: Acute oxaliplatin neurotoxicity has been shown to be predictive of chronic oxaliplatin neuropathy. A recent study by Attal et al showed that tQST (thermal quantitative sensory testing) at cycle 4 provides a noninvasive method for predicting chronic neuropathy. A high risk population defined as those experiencing pain with a ≥ 20 degree cold stimulus had an OR of 39 for developing a severe chronic neuropathy at 1 year. Our study was designed to test the utility of tQST at earlier time points for predicting chronic neuropathy. Methods: Gastrointestinal cancer patients receiving FOLFOX were evaluated over a 1 year period for the development of acute and chronic oxaliplatin neurotoxicity: before starting FOLFOX, 1 hour into oxaliplatin infusion, before cycles 2, 4 and 12, and 1 year after start of treatment. Patients underwent a series of QSTs to measure thermal and mechanical sensitivities, fine motor skills, vibration detection, validated questionnaires, and presence of hyperalgesia. Results: Preliminary analysis of 13 patients using cycle 4 data as a surrogate for chronic neuropathy shows that cold pain (the temperature at which subjects report pain) prior to starting FOLFOX and at cycle 2 is predictive of cold pain at cycle 4, rs = 0.67 (p=.01) and 0.49 (p=0.09), respectively. There is a significant difference in cold pain across all time points between high and low risk populations(p=0.02 at baseline, p=0.04 during cycle 1, p=0.08 at cycle 2, and p=0.03 at cycle 4). Correlation between cycles 1 and 4 is seen for changes in cold sensitivity from baseline, rs = 0.52 (p=0.07). Conclusions: Baseline tQST correlates to cycle 4 measurements and may be an early predictor of patients at the highest risk for chronic neuropathy. These preliminary data indicate an inherent, pre-existing sensitivity to oxaliplatin induced chronic neuropathy for high risk patients which can be detected with tQST. Early identification of these patients can allow for preventive measures to decrease the incidence of this debilitating chronic adverse effect of oxaliplatin. A larger biomarker validation study is planned using tQST to stratify patients into high and low risk.

Effects of the endocannabinoid transport inhibitors AM404 and UCM707 on diabetic neuropathy in rats

1. Diabetic rats display increased pain responses following injection of formalin into the paw, suggesting the presence of hyperalgesia. In the present study, we investigated the efficacy of the systemic administration of the endocannabinoid transport inhibitors UCM707 and AM404 (1, 10 and 50 mg/kg, i.p.) on hyperalgesia during the formalin test in streptozocin (STZ)-induced diabetic rats. 2. Nociceptive testing was performed in male adult Wistar rats 4 weeks after the onset of hyperglycaemia. At the end of the experiment, all rats were weighed and then underwent plasma glucose measurements. 3. Diabetes caused significant hyperalgesia during both phases of the formalin test. At 10 and 50 mg/kg, both UCM707 and AM404 reversed chemical hyperalgesia in diabetic rats. UCM707 (10 and 50 mg/kg) caused less intensive nociceptive behaviour during both phases of the test, whereas AM404 (10 and 50 mg/kg) only affected pain scores during Phase 1 of the formalin test. At 1 mg, neither drug had any effect on pain behaviour in control and diabetic groups compared with their respective controls. Neither UCM707 nor AM404 had any effect on bodyweight or plasma glucose levels of treated compared with non-treated rats at any of the doses tested. 4. The results of the present study indicate that systemic administration of UCM707 and AM404 is effective in ameliorating chemical hyperalgesia in STZ-diabetic rats. Thus, endocannabinoid transport inhibitors may have potential in the treatment of painful diabetic neuropathy.

Crotalphine induces potent antinociception in neuropathic pain by acting at peripheral opioid receptors

Neuropathic pain is an important clinical problem and it is usually resistant to the current therapy. We have recently characterized a novel analgesic peptide, crotalphine, from the venom of the South American rattlesnake Crotalus durissus terrificus. In the present work, the antinociceptive effect of crotalphine was evaluated in an experimental model of neuropathic pain induced in rats by chronic constriction of sciatic nerve. The effect of the peptide was compared to that induced by the crude venom, which confirmed that crotalphine is responsible for the antinociceptive effect of the crotalid venom on neuropathic pain. For characterization of neuropathic pain, the presence of hyperalgesia, allodynia and spontaneous pain was assessed at different times after nerve constriction. These phenomena were detected 24 h after surgery and persisted at least for 14 days. The pharmacological treatments were performed on day 14 after surgery. Crotalphine (0.2–5 µg/kg) and the crude venom (400–1600 µg/kg) administered p.o. inhibited hyperalgesia, allodynia and spontaneous pain induced by nerve constriction. The antinociceptive effect of the peptide and crude venom was long lasting, since it was detected up to 3 days after treatment. Intraplantar injection of naloxone (1 µg/paw) blocked the antinociceptive effect, indicating the involvement of opioid receptors in this phenomenon. Gabapentin (200 mg/kg, p.o.), and morphine (5 mg/kg, s.c.), used as positive controls, blocked hyperalgesia and partially inhibited allodynia induced by nerve constriction. These data indicate that crotalphine induces a potent and long lasting opioid antinociceptive effect in neuropathic pain that surpasses that observed with standard analgesic drugs.

Neuropathic pain correlates with myelinated fibre loss and cytokine profile in POEMS syndrome

Objective:To reveal characteristic clinicopathological correlates of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome.Methods:The clinical features of 22 patients with POEMS syndrome were investigated and correlated with the...

Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis.

The aim of this study was to investigate a possible role for nerve growth factor (NGF) in the mechanism of pain and hyperalgesia induced by deep adenomyotic nodules and other forms of endometriosis and to clarify the relationship between endometriotic lesions and the surrounding nerves. Endometriotic lesions (deep adenomyotic nodules, peritoneal endometriosis, ovarian endometriosis) and eutopic endometrium were obtained from 51 patients presenting with pain. Patients were allocated to two groups (group 1: patients with a deep adenomyotic nodule (n = 23); group 2: patients with peritoneal and/or ovarian endometriosis but without deep adenomyotic nodule (n = 28). Immunohistochemistry with antibodies against NGF, NGF specific tyrosine-kinase receptor (Trk-A) and S-100 protein was performed. Results were expressed as mean H-scores +/- SD, and correlated with the presence of hyperalgesia. The percentage of patients presenting hyperalgesia at physical examination was significantly higher in group 1 (96%) than in group 2 (11%) (P < 0.001). NGF expression was significantly stronger in deep adenomyotic nodules (DAN) than in ovarian (OE) and peritoneal endometriosis (PE), both in the proliferative phase in the glands [DAN: 226 +/- 18; OE: 140 +/- 9 (P < 0.001); PE: 110 +/- 7 (P < 0.001)] and in the stroma [(DAN: 204 +/- 21; OE: 125 +/- 15 (P < 0.001); PE: 100 +/- 9 (P < 0.01)]. NGF expression in DAN is also significantly stronger than in OE and PE in the secretory phase in the glands [DAN:181 +/- 32; OE: 85 +/- 3.3 (P < 0.001); PE: 65 +/- 9 (P < 0.001)] and in the stroma [DAN: 173 +/- 28; OE: 85 +/- 3.7 (P < 0.001); PE: 35 +/- 13 (P < 0.001)]. Perineurial and intraneurial invasion by endometriotic lesions were found only in deep adenomyotic nodules and not in the other forms of endometriosis. The specific receptor for NGF (Trk-A) is expressed in all the nerves that were included in the biopsies. These results suggest a role of NGF in endometriotic pain and hyperalgesia in deep adenomyotic nodules. The strong expression of the NGF-TrkA pathway in deep adenomyotic nodules could explain why this type of lesion infiltrates in richly innervated anatomical sites.

Evaluation of the efficacy of a bioerodible bupivacaine polymer system on antinociception and inflammatory mediator release

Pain due to tissue injury is often characterized by the presence of hyperalgesia and allodynia. It is hypothesized that these perceptual states are mediated by sensitization of peripheral terminals of primary afferent neurons together with several changes in the central nervous system. This provides a rationale for preemptive analgesia, whereby the blockade of primary afferent input prior to injury may result in a reduction of post-injury pain. One approach for prolonged blockade of primary afferent input is the use of bioerodible polymer systems providing regulated release of local anesthetics. Bioerodible polymer systems offer the theoretical advantage of controlled drug delivery maintained over prolonged periods. Local application of this system to the inflamed tissue compartment permits the use of smaller total drug doses. This may minimize systemic side effects, while maintaining prolonged peripherally-mediated antinociception. In the present study, we evaluated the effects of a bioerodible polymer/bupivacaine system (PLGA/bupivacaine) on several indices of inflammation and on hindpaw levels of the inflammatory mediators, substance P and bradykinin in the complete Freund's adjuvant model. We observed that PLGA/bupivacaine reduces inflammatory hyperalgesia, edema and hyperthermia in a temporal and dose-related fashion in awake animals. Moreover, we demonstrated that PLGA/bupivacaine has a prolonged inhibitory effect on the tissue levels of substance P and bradykinin in the inflamed hindpaws. The results of these studies clearly indicate the potential therapeutic utility of the PLGA bupivacaine system, with the single dose administration producing a prolonged suppression of hyperalgesia, edema and biochemical indices of inflammation.

Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: blockade by MK-801 but not naloxone

Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl- d-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1–17), dynorphin A(1–13), dynorphin A(2–17) or dynorphin A(2–13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1–17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1–13) or dynorphin A(2–17) or dynorphin A(2–13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1–17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1–17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a ‘neuropathic’ state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.

Neurological Causes of Cervicobrachial Pain

The objective was to investigate the presence of cutaneous allodynia and hyperalgesia in the trigeminal and extra-trigeminal areas, as a surrogate for central sensitization (CS), in women with a painful temporomandibular disorder (TMD) and without other painful conditions. Painful TMDs, depression, and non-specific physical symptoms (NSPS) were classified according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). The amount of pain in the trigeminal and extra-trigeminal areas was determined using a visual analogue scale (0–100 mm) after the application of a vibrotactile stimulus and assessment of the pressure pain threshold (PPT). Statistical tests (Fisher's, χ2, and Mann–Whitney) were performed, with a significance level of 5%. The sample comprised 45 women (mean age 37.5 years; 16 with a painful TMD) who were free of any headache, fibromyalgia, or other painful condition. Painful TMD was associated with higher pain sensitivity and lower PPT values in the trigeminal (P < 0.01) and extra-trigeminal regions (P < 0.01). The presence of depression contributed significantly to increased pain sensitivity. The presence of hyperalgesia and allodynia in both the trigeminal and extra-trigeminal regions among women with a painful TMD indicated the presence of CS. Changes involving the central nervous system should be considered during the evaluation and management of patients with a painful TMD.