Pain
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Cold allodynia, pain in response to cooling, occurs during or within hours of oxaliplatin infusion and is thought to arise from a direct effect of oxaliplatin on peripheral sensory neurons. To characterize the pathophysiological mechanisms underlying acute oxaliplatin-induced cold allodynia, we established a new intraplantar oxaliplatin mouse model that rapidly developed long-lasting cold allodynia mediated entirely through tetrodotoxin-sensitive Nav pathways. ⋯ Intraplantar injection of the Nav1.6 activator Cn2 elicited spontaneous pain, mechanical allodynia, and enhanced 4-aminopyridine-induced cold allodynia. These findings provide behavioural evidence for a crucial role of Nav1.6 in multiple peripheral pain pathways including cold allodynia.
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The natural hormone uroguanylin regulates intestinal fluid homeostasis and bowel function through activation of guanylate cyclase-C (GC-C), resulting in increased intracellular cyclic guanosine-3',5'-monophosphate (cGMP). We report the effects of uroguanylin-mediated activation of the GC-C/cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress-induced visceral hypersensitivity. In vitro exposure of intestinal Caco-2 cells to uroguanylin stimulated bidirectional, active extracellular transport of cGMP into luminal and basolateral spaces. cGMP transport was significantly and concentration dependently decreased by probenecid, an inhibitor of cGMP efflux pumps. ⋯ The antihyperalgesic effects of cGMP were not associated with increased colonic spasmolytic activity, but were linked to significantly decreased firing rates of TNBS-sensitized colonic afferents in rats in response to mechanical stimuli. In conclusion, these data suggest that the continuous activation of the GC-C/cGMP pathway along the intestinal tract by the endogenous hormones guanylin and uroguanylin results in significant reduction of gastrointestinal pain. Extracellular cGMP produced on activation of GC-C is the primary mediator in this process via modulation of sensory afferent activity.
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Randomized Controlled Trial
Specifying the nonspecific components of acupuncture analgesia.
It is well known that acupuncture has pain-relieving effects, but the contribution of specific and especially nonspecific factors to acupuncture analgesia is less clear. One hundred one patients who developed pain of ≥ 3 on a visual analog scale (VAS, 0 to 10) after third molar surgery were randomized to receive active acupuncture, placebo acupuncture, or no treatment for 30 min with acupuncture needles with potential for double-blinding. Patients' perception of the treatment (active or placebo) and expected pain levels (VAS) were assessed before and halfway through the treatment. ⋯ Expected pain levels accounted for significant and progressively larger amounts of the variance in pain ratings after both active and placebo acupuncture (up to 69.8%). This is the first study to show that under optimized blinding conditions, nonspecific factors such as patients' perception of and expectations toward treatment are central to the efficacy of acupuncture analgesia and that these factors may contribute to self-reinforcing effects in acupuncture treatment. To obtain an effect of acupuncture in clinical practice, it may therefore be important to incorporate and optimize these factors.
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Randomized Controlled Trial
Association between clinical signs assessed by manual segmental examination and findings of the lumbar facet joints on magnetic resonance scans in subjects with and without current low back pain: A prospective, single-blind study.
The relevance of magnetic resonance imaging (MRI) findings such as facet joint (FJ) effusion and edema in low back pain (LBP) is still unknown. Therefore, we prospectively evaluated the presence of these MRI findings in the lumbar spine (Th12-S1) and their association with pain evoked by manual segmental FJ provocation tests (spinal percussion, springing, and segmental rotation tests) in 75 subjects with current LBP (≥30 days in the past 3 months) compared with 75 sex- and age-matched control subjects. FJs were considered painful, if ≥ 1 provocation test triggered LBP. ⋯ True-positive findings occurred in 16% of LBP FJs and in 2% of control FJs (P<0.01); 46 LBP subjects (61%) and 9 control subjects (12%, P<0.01) had true-positive findings. Pain on provocation and FJ effusion and/or edema were significantly correlated only in patients with LBP. In conclusion, only true-positive findings (ie, concurrent effusion and/or edema and positive provocation test results in the same FJ) discriminate well enough between control subjects and subjects with current LBP, whereas neither effusion and/or edema nor FJ provocations tests alone are suitable to detect suspected FJ arthropathy.
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Headaches can be evoked by activation of meningeal nociceptors, but an involvement of pericranial tissues is debated. We aimed to examine a possible extracranial innervation by meningeal afferents in the rat. For in vivo neuronal tracing, dextran amines were applied to the periosteum underlying the temporal muscle. ⋯ Noxious stimulation of the temporal muscle caused CGRP release from the dura mater and elevated meningeal blood flow. Collaterals of meningeal nerve fibers project through the skull, forming functional connections between extra- and intracranial tissues. This finding offers a new explanation of how noxious stimulation of pericranial tissues can directly influence meningeal nociception associated with headache generation and why manual therapies of pericranial muscles may be useful in headaches.