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IntroductionChronic pain and the pattern of opioid use after skeletal fractures has been a neglected topic in pain medicine. Pelvic and in particular acetabular fractures represent some of the most troublesome injuries for patients with a high incidence of chronic pain after fracture. We examined the long-term opioid analgesic use among patients with acetabular fractures and analysed if potential risk factors would predict a prolonged opioid therapy.Patients and methodsData were extracted from medical databases such as the Swedish National Hospital Discharge Register and the National Pharmacy Register. The study period was 2005–2008. Kaplan–Meier analysis constructed the cumulative opioid consumption with 95% confidence intervals (CI). Cox multiple-regression model was used to study risk factors for a prolonged opioid prescription after admission for fracture. An age- and sex-matched control group was included for comparisons.ResultsWe identified 1017 patients with isolated acetabular fractures. The proportion of dispensing opioids for these patients was 39%, which was 7 times higher than in the age- and sex-matched non-fracture controls (n=5077). The median follow-up time was 14 (interquartile range [IQR] 5–24) months. Most patients with opioid use after fracture were male (60%) and the median age was 76 (IQR 61–85) years. The leading mechanism of injury was fall on the same level (52%). At 6 and 12 months after fracture, 41% (95% CI 36–47) and 33% (28–39) were still treated with opioids. The multiple Cox regression-analysis (adjusted for age, sex, type of treatment, and mechanism of injury) revealed that younger patients (age

Numerous in vitro studies suggest that inflammation is associated with enhanced release of substance P (SP) in the dorsal horn. To test the hypothesis that inflammation increases the evoked concentration of SP in the intact animal, we used in vivo microdialysis with a highly sensitive radioimmunoassay to monitor SP-like immunoreactivity (SP-LI) in the dorsal horn. Seven days after the induction of persistent unilateral inflammation with hindpaw injection of complete Freund's adjuvant, perfusion of the microdialysis probe with 10 microM capsaicin (a concentration which failed to induce SP-LI release in rats without inflammation) induced a significant increase of microdialysate SP-LI. Inclusion of an NMDA antagonist in the perfusion fluid completely blocked this capsaicin-evoked SP release. Administration of a five-fold higher dose of capsaicin did not further increase SP release. These results in a rat model of chronic arthritis suggest that persistent inflammatory signaling facilitates capsaicin-evoked SP release in the dorsal horn in vivo.

The aim of the present in vivo microdialysis study was to determine the possible contribution of N -methyl- d -aspartate (NMDA) or α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) receptors to capsaicin-induced release of substance P-like immunoreactivity (SP-LI) in the dorsal horn of the rat. Perfusion of a microdialysis probe with capsaicin (50 or 100 μM) induced a significant eight-fold increase of the extracellular SP-LI level. The capsaicin (50 μM)-evoked release of SP-LI was blocked by spinal administration of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (D-APV; 5 mM), but not by the AMPA/KA antagonist 6-nitro-7-sulphamoylbenzo[ f ]quinoxaline-2,3-dione disodium (NBQX; 0.5 mM). In contrast, the SP-LI release induced by 100 μM capsaicin could not be prevented by D-APV (10 mM) or NBQX (0.5 mM). The data suggest that the spinal SP-LI release induced by a moderate concentration of capsaicin is in part dependent on the release of glutamate acting on NMDA receptors.

The microdialysis technique, used to monitor extracellular levels of transmitter substances in the central nervous system of laboratory animals as a reflection of transmitter release, is based on the ability of neurotransmitters to diffuse in the extracellular fluid from the site of release and to cross a semipermeable dialysis membrane. Even though the surgical procedure is not very complicated, the detection of released substances in the recovered dialysate may be difficult. Especially, the measurement of neuropeptide release is limited by the low extracellular concentration and of low recovery as compared to, for example, monoamines. Thus, for example, cholecystokinin (CCK), which is the most abundant neuropeptide in the central nervous system, is found at concentrations that are several orders of magnitude lower than those of classical transmitters. Therefore a highly sensitive detection method is of utmost importance. In the dorsal horn of the spinal cord CCK is found mainly in interneurons and in terminals of descending fibers. CCK seems to be involved in nociceptive transmission and CCK attenuates morphine-induced antinociception. We here describe in vivo microdialysis in the lumbar dorsal horn of the rat with subsequent quantification of the level of CCK-like immunoreactivity (-LI) by a highly sensitive radioimmunoassay. Theme: Neurotransmitters, modulators, transporters, and receptors Topic: Peptides: anatomy and physiology

An increased expression of cholecystokinin (CCK) messenger RNA (mRNA) as well as CCK-B receptor mRNA in dorsal root ganglion (DRG) cells following peripheral axotomy has previously been demonstrated. In the present in vivo microdialysis study, the effect of unilateral sciatic nerve section on basal and potassium-induced release of CCK-like (CCK-LI) immunoreactivity in the rat dorsal horn was investigated. We also compared the effects of the CCK-B receptor antagonist CI988 on basal and potassium-stimulated CCK-LI release in intact animals and in chronically axotomized rats. Perfusion of the microdialysis probe with KCl (100 mM) induced a more than 6-fold increase of the extracellular level of CCK-LI in control animals. In contrast, following unilateral sciatic nerve section the same KCl stimulation failed to evoke a release of CCK-LI ipsilaterally. However, after systemic administration of CI988 (1 mg kg-1, i.v.), 100 mM KCl induced a significant increase of the extracellular CCK-LI level in axotomized rats, similar to that observed in control animals. In control animals no effect of CI988 on KCl-stimulated CCK-LI release could be detected. CI988 by itself had no influence on the extracellular CCK-LI level in either nerve injured or control animals. The present data suggest that axotomy reduces the release of CCK-like immunoreactivity in the spinal cord by a mechanism involving the CCK-B receptor binding site.

The midbrain periaqueductal gray matter (PAG) is an important region for endogenous pain suppression. Nerve terminals containing opioid peptides and neurotensin (NT), as well as high densities of opioid- and NT-receptors, have been demonstrated in the ventromedial PAG. Local administration of opioids or NT in this region induces antinociception in experimental animals. In the present microdialysis study, the effect of opioids on the release of NT in the ventromedial PAG was investigated. Perfusion of the microdialysis probe with 10 microM morphine induced a significant increase (P0.05; n = 5) of the extracellular level of NT-like immunoreactivity (NT-LI), while perfusion with a 10-fold higher concentration of morphine had no significant effect on the NT-LI release in the PAG. Also perfusion of the dialysis probe with the mu-opioid receptor-specific agonist [D-Ala2-N-Me-Phe4-Gly5-ol]-enkephaline (DAGO) (1 or 100 microM) induced a significant (P0.05; n = 7-9) increase of the NT-LI level. The increase in NT-LI release in response to 1 microM DAGO was both calcium-dependent and naloxone-reversible. Since opioid agonists generally inhibit neuronal activity, an indirect mechanism, involving inhibition of tonically active inhibitory neurons, e.g. gamma-aminobutyric acid (GABA) neurons, could be of importance for the opioid induced release of NT. However, local administration in the PAG of the GABA(A) antagonist bicuculline (0.1-10 microM) or the GABA(A) agonist muscimol (1-100 microM) had no significant effect on the extracellular NT-LI level in the PAG, suggesting that GABAergic mechanisms are not involved in the opioid-induced release of NT-LI. In conclusion, the present data provide in vivo evidence that mu-opioid receptors mediate stimulation of neurotensin release in the PAG.

The use of capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) for the analysis of microdialysate samples from the periaqueductal grey matter (PAG) of freely moving rats is described. By employing 3-(4-carboxybenzoyl)-2-quinoline-carboxaldehyde (CBQCA) as a derivatization agent, we simultaneously monitored the concentrations of 8 amino acids (arginine, glutamine, valine, gamma-amino-n-butyric acid (GABA), alanine, glycine, glutamate, and aspartate), with nanomolar and subnanomolar detection limits. Two of the amino acids (GABA and glutamate) were analysed in parallel by conventional high-performance liquid chromatography (HPLC) in order to directly compare the two analytical methods. Other CE methods for analysis of microdialysate have been previously described, and this improved method offers greater sensitivity, ease of use, and the possibility to monitor several amino acids simultaneously. By using this technique together with an optimised form of microdialysis technique, the tiny sample consumption and the improved detection limits permit the detection of fast and transient transmitter changes.

The effect of repeated electroconvulsive shock (five shocks during 10 days) on preprocholecystokinin and preprotachykinin-A messenger RNA expression was studied in the mesencephalic periaqueductal gray and adjacent areas of rat using in situ hybridization histochemistry with specific oligonucleotide probes. An increased number of preprocholecystokinin and preprotachykinin-A messenger RNA hybridization positive neurons (+ 30% and +47%, respectively) in the Edinger-Westphal nucleus was observed following repeated electroconvulsive shock. In addition, both preprocholecystokinin and preprotachykinin-A messenger RNA expression, measured as grain density over single neurons, was significantly increased (+37% and +45%, respectively). The results indicate that cholecystokimn- and substance P-contaimng neurons in the Edinger-Westphal nucleus are activated by repeated electroconvulsive shock, which may be related to the antidepressant and analgesic effects of electroconvulsive shock treatment.