The journal of pain : official journal of the American Pain Society
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A single gene deletion causes lack of leptin and obesity in B6.V-Lep(ob) (obese; ob) mice compared with wild-type C57BL/6J (B6) mice. This study compared the phenotype of nociception and supraspinal antinociception in obese and B6 mice by testing 2 hypotheses: (1) microinjection of cholinomimetics or an adenosine receptor agonist, but not morphine, into the pontine reticular formation (PRF) is antinociceptive in B6 but not obese mice, and (2) leptin replacement in obese mice attenuates differences in nociceptive responses between obese and B6 mice. Adult male mice (n = 22) were implanted with microinjection guide tubes aimed for the PRF. The PRF was injected with neostigmine, carbachol, nicotine, N(6)-p-sulfophenyladenosine (SPA), morphine, or saline (control), and latency to paw withdrawal (PWL) from a thermal stimulus was recorded. B6 and ob mice did not differ in PWL after saline microinjection into the PRF. Neostigmine, carbachol, and SPA caused PWL to increase significantly in B6 but not obese mice. An additional 15 obese mice were implanted with osmotic pumps that delivered leptin for 7 days. Leptin replacement in obese mice restored the analgesic effect of PRF neostigmine to the level displayed by B6 mice. The results show for the first time that leptin significantly alters supraspinal cholinergic antinociception. ⋯ This study specifies a brain region (the pontine reticular formation), cholinergic neurotransmission, and a protein (leptin) modulating thermal nociception. The results are relevant for efforts to understand the association between obesity, disordered sleep, and hyperalgesia.
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Randomized Controlled Trial
An investigation of the hypoalgesic effects of TENS delivered by a glove electrode.
This randomized, placebo-controlled, blinded study investigated the hypoalgesic effects of high-frequency transcutaneous electrical nerve stimulation (TENS) delivered via a glove electrode compared with standard self-adhesive electrodes. Fifty-six TENS-naïve, healthy individuals (18 to 50 years old; 28 men, 28 women) were randomly allocated to 1 of 4 groups (n = 14 per group): glove electrode; placebo TENS using a glove electrode; standard electrode; and no treatment control. Active TENS (continuous stimulus, 100 Hz, strong but comfortable intensity) was applied to the dominant forearm/hand for 30 minutes. Placebo TENS was applied using a burst stimulus, 100-Hz frequency, 5-second cycle time for 42 seconds, after which the current amplitude was automatically reset to 0 mA. Pressure pain thresholds (PPTs) were recorded from 3 points on the dominant and nondominant upper limbs before and after TENS. Statistical analyses of dominant PPT data using between-within groups ANOVA showed significant differences between groups at all 3 recording points (P = .01). Post hoc Scheffe tests indicated no significant difference between the standard electrode and glove electrode groups. There was a significant hypoalgesic effect in the standard electrode group compared with the control group and between the glove electrode group and both the control and placebo TENS groups. There was no significant interactive effect between time and group at any of the recording points (P > .05). ⋯ This study presents a comparison of the hypoalgesic effects of 2 different types of TENS electrode, a novel glove electrode and standard self-adhesive rectangular electrodes. The glove electrode provides a larger contact area with the skin, thereby stimulating a greater number of nerve fibers. The results show that both electrodes have similar hypoalgesic effects and therefore give the clinician another choice in electrode.
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Understanding the genetic basis of human variations in pain is critical to elucidating the molecular basis of pain sensitivity, variable responses to analgesic drugs, and, ultimately, to individualized treatment of pain and improved public health. With the help of recently accumulated knowledge and advanced technologies, pain researchers hope to gain insight into genetic mechanisms of pain and eventually apply this knowledge to pain treatment. ⋯ We critically reviewed the published literature to examine the strength of evidence supporting genetic influences on clinical and human experimental pain. Based on this evidence and the experience of false associations that have occurred in other related disciplines, we provide recommendations for avoiding pitfalls in pain genetic research.
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Endogenous anandamide and cannabinoid receptor-2 contribute to electroacupuncture analgesia in rats.
Acupuncture is widely used clinically to treat acute and chronic pain conditions, but the mechanisms underlying its effect are not fully understood. Although endocannabinoids are involved in modulation of nociception in animal models and in humans, their role in acupuncture analgesia has not been assessed. In this report, we determined the effect of electroacupuncture (EA) on the level of anandamide in the skin tissue and the role of cannabinoid CB1 and CB2 receptors in the analgesic effect of EA in an animal model of inflammatory pain. Inflammatory pain was induced by local injection of complete Freund's adjuvant (CFA) into the hind paw of rats. Thermal hyperalgesia was tested with a radiant heat stimulus, and mechanical allodynia was quantified with von Frey filaments. The anandamide concentration in the skin tissue was measured by using high-performance liquid chromatography. EA, applied to GB30 and GB34, at 2 and 100Hz significantly reduced thermal hyperalgesia and mechanical allodynia induced by CFA injection. Compared with the sham group, EA significantly increased the anandamide level in the inflamed skin tissue. Local pretreatment with a specific CB2 receptor antagonist, AM630, significantly attenuated the antinociceptive effect of EA. However, the effect of EA was not significantly altered by AM251, a selective CB1 receptor antagonist. These findings suggest that EA potentiates the local release of endogenous anandamide from inflamed tissues. Activation of peripheral CB2 receptors contributes to the analgesic effect of EA on inflammatory pain. ⋯ This study shows that electroacupuncture increases the anandamide level in inflammatory skin tissues, and CB2 receptors contribute to the analgesic effect of electroacupuncture in a rat model of inflammatory pain. This information improves our understanding of the mechanisms involved in the analgesic effect of acupuncture.
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In animal studies, thermal sensitivity is mostly evaluated on the basis of nociceptive reaction latencies in response to a given thermal aversive stimulus. However, these techniques may be inappropriate to differentiate allodynia from hyperalgesia or to provide information differentiating the activation of nociceptor subtypes. The recent development of dynamic hot and cold plates, allowing computer-controlled ramps of temperature, may be useful for such measures. In this study, we characterized their interest for studying thermal nociception in freely moving mice and rats. We showed that escape behavior (jumps) was the most appropriate parameter in C57Bl/6J mice, whereas nociceptive response was estimated by using the sum of paw lickings and withdrawals in Sprague-Dawley rats. We then demonstrated that this procedure allows the detection of both thermal allodynia and hyperalgesia after peripheral pain sensitization with capsaicin in mice and in rats. In a condition of carrageenan-induced paw inflammation, we observed the previously described thermal hyperalgesia, but we also revealed that rats exhibit a clear thermal allodynia to a cold or a hot stimulus. These results demonstrate the interest of the dynamic hot and cold plate to study thermal nociception, and more particularly to study both thermal allodynia and hyperalgesia within a single paradigm in awake and freely moving rodents. ⋯ Despite its clinical relevance, thermal allodynia is rarely studied by researchers working on animal models. As shown after stimulation of capsaicin-sensitive fibers or during inflammatory pain, the dynamic hot and cold plate validated in the present study provides a useful tool to distinguish between thermal allodynia and thermal hyperalgesia in rodents.