Pain
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The current study assessed whether the chronic constriction injury (CCI) model of neuropathic pain causes depression-like behaviour in animals, and if this depression-like behaviour can be reversed by anti-nociceptive and/or antidepressant drugs. CCI of the sciatic nerve in rats was selected as a neuropathic pain model, mechanical hypersensitivity was assessed by punctuate mechanical stimuli, and depression-like behaviour was evaluated in the forced swimming test (FST) measuring the time of immobility, climbing and swimming. The CCI rats displayed a significant mechanical hypersensitivity (sham 27+/-2g, CCI 12+/-2g; P<0.001) and a significant increase in time of immobility (sham 133+/-14s, CCI 201+/-9s; P<0.001). ⋯ In contrast in CCI animals the cannabinoid CB2-selective agonist GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone) (30 mg/kg) significantly attenuated immobility (CCI+vehicle 191+/-7s, GW405833 145+/-14s; P<0.01) and mechanical hypersensitivity (CCI+vehicle 15+/-1g, CCI+GW405833 24+/-1g; P<0.001). Moreover, differently from desipramine, GW405833 did not change the climbing behaviour. These data suggest that rats subjected to the CCI model of neuropathic pain develop depression-like behaviour, which can be reversed by appropriate anti-nociceptive treatment.
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Controlled Clinical Trial
Moderation and mediation in the psychological and drug treatment of chronic tension-type headache: the role of disorder severity and psychiatric comorbidity.
We evaluated two putative moderators of treatment outcome as well as the role of Headache Management Self-Efficacy (HMSE) in mediating treatment outcomes in the drug and non-drug treatment of chronic tension-type headache (CTTH). Subjects were 169 participants (M=38 yrs.; 77% female; M headache days/mo.=22) who received one of four treatments in the treatment of CTTH trial (JAMA, 2001; 285: 2208-15): tricyclic antidepressant medication, placebo, (cognitive-behavioral) stress-management therapy plus placebo, and stress-management therapy plus antidepressant medication. Severity of CTTH disorder and the presence of a psychiatric (mood or anxiety) disorder were found to moderate outcomes obtained with the three active treatments and with placebo, as well as to moderate the role of HMSE in mediating improvements. ⋯ HMSE mediated treatment outcomes in the two stress-management conditions, but the pattern of HMSE mediation was complex, varying with the treatment condition, the outcome measure, and the moderator variable. Irrespective of the severity of the CTTH disorder HMSE fully mediated observed improvements in headache activity in the two stress-management conditions. However, for patients with a mood or anxiety disorder HMSE only partially mediated improvements in headache disability, suggesting an additional therapeutic mechanism is required to explain observed improvements in headache disability in the two stress-management conditions.
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Randomized Controlled Trial Comparative Study
Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis.
While topical non-steroidal anti-inflammatory drugs are considered safe, their long-term efficacy for osteoarthritis has been suspect. We conducted a 12-week, double-blind, double-dummy, randomized controlled trial of topical diclofenac (TDiclo) in a vehicle solution containing dimethyl sulfoxide (DMSO) in 775 subjects with radiologically confirmed, symptomatic primary osteoarthritis of the knee. This 5-arm study compared TDiclo with a placebo solution, the DMSO vehicle, oral diclofenac (ODiclo) and the combination of TDiclo+ODiclo for relieving the signs and symptoms of knee osteoarthritis. ⋯ Addition of TDiclo to ODiclo did not increase the incidence of systemic adverse events. TDiclo in DMSO vehicle is an effective treatment option for knee osteoarthritis with efficacy similar to, but tolerability better than ODiclo. DMSO vehicle was no more efficacious than placebo.
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Although N-methyl-d-aspartate (NMDA) receptor antagonists potentiate antinociceptive effects induced by various exogenous opioids at the spinal, supraspinal, or peripheral level, less is known regarding the interaction between NMDA and endogenous opioids in antinociception. We therefore assessed the effects of NMDA receptor antagonists on endogenous opioids in antinociception at the peripheral level by testing the ability of the locally administered receptor antagonists to modify pain-related behavior induced by carrageenan injection into the knee joint. The NMDA receptor antagonist AP-5 or the exogenous opioid morphine was injected intra-articularly before carrageenan injection and 5h after carrageenan injection, respectively. ⋯ Intriguingly, injection of naloxone 5h after carrageenan injection reversed the antinociceptive effects of AP-5 pre-treatment, although naloxone alone had no effect on carrageenan-induced pain-related behavior. Western blots showed that AP-5 pre-treatment followed by carrageenan injection resulted in a higher level of beta-endorphin protein in the DRG and saphenous nerve, but not in the synovial membrane, than that observed following saline control treatment. These results suggest that inhibition of the NMDA receptor unmasks antinociception induced by endogenous opioids at the peripheral level, partly through the increased protein level of the endogenous mu-opioid peptide beta-endorphin in DRG and saphenous nerve.
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We evaluated the role of sigma(1) receptors on capsaicin-induced mechanical hypersensitivity and on nociceptive pain induced by punctate mechanical stimuli, using wild-type and sigma(1) receptor knockout (sigma(1)-KO) mice and selective sigma(1) receptor-acting drugs. Mutation in sigma(1)-KO mice was confirmed by PCR analysis of genomic DNA and, at the protein level, by [(3)H](+)-pentazocine binding assays. Both wild-type and sigma(1)-KO mice not treated with capsaicin showed similar responses to different intensities of mechanical stimuli (0.05-8 g force), ranging from innocuous to noxious, applied to the hind paw. ⋯ The effects of the sigma(1) antagonists were reversed by the sigma(1) agonist PRE-084 (32 mg/kg, s.c.). None of the drugs tested modified the responses induced by a painful mechanical punctate stimulus (4 g force) in nonsensitized animals. These results suggest that sigma(1) receptors are essential for capsaicin-induced mechanical hypersensitivity, but are not involved in mechanical nociceptive pain.