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The purpose of this article was to examine age-related changes in conditioned pain modulation (CPM) and temporal summation of pain (TS) using meta-analytic techniques. Five electronic databases were searched for studies that compared measures of CPM and TS between healthy, chronic pain-free younger, middle-aged, and older adults. Eleven studies were included in the final review for TS and 11 studies were included in the review of CPM. The results suggested a moderate magnitude of difference in TS between younger adults and middle-aged/older adults, with the older cohorts exhibiting enhanced TS of pain. Considerable variability existed in the magnitude of the effects sizes, which was likely due to the different experimental methodology used across studies (i.e., inter-stimulus interval, stimulus type, body location). In regards to CPM, the data revealed a large magnitude of difference between younger and older adults, with younger adults exhibiting more efficient pain inhibition. Differences in CPM between middle-aged and older adults were minimal. The magnitude of pain inhibition during CPM in older adults may depend on the use of concurrent vs. non-concurrent protocols. In summary, the data provided strong quantitative evidence of a general age-related decline in endogenous pain modulatory function as measured by TS and CPM. PERSPECTIVE: This review compared conditioned pain modulation and temporal summation of pain between younger, middle-aged, and older adults. These findings enhance our understanding of the decline in endogenous pain modulatory function associated with normal aging.
Learn More >The development of multitarget opioid drugs has emerged as an attractive therapeutic strategy to eliminate opioid-related side effects. Our previous study developed a series of opioid and neuropeptide FF (NPFF) pharmacophore-containing chimeric peptides, including DN-9 (Tyr-D.Ala-Gly-NMe.Phe-Gly-Pro-Gln-Arg-Phe-NH), which produced potent nontolerance forming analgesia at the supraspinal level. In the present study, the antinociceptive effects of DN-9 in a series of preclinical pain models and the potential side-effects were investigated at the spinal level in mice. In the tail-flick test, intrathecal injection of DN-9 produced potent analgesia with an ED value at 1.33 pmol, and the spinal antinociception of DN-9 was mainly mediated by μ- and κ-opioid receptors. In addition, DN-9-induced spinal antinociception was augmented by the NPFF receptors antagonist. Furthermore, DN-9 could decrease both the frequency and amplitude of sEPSCs in lamina IIo neurons of the spinal cord, which were mediated by opioid receptors. In contrast to morphine, chronic intrathecal treatments with DN-9 did not induce analgesic tolerance, c-Fos expression or microglial activation. Intrathecal injection of DN-9 showed potent analgesia with antinociceptive ED values between 0.66 and 55.04 pmol in different pain models, including the formalin test, acetic acid-induced writhing test, carrageen-induced inflammatory pain and neuropathic pain. Moreover, DN-9 did not show side effects in locomotor function and coordination, gastrointestinal transit inhibition, the cardiovascular system, and body temperature regulation at antinociceptive doses. Taken together, the present study showed DN-9 produced effective, nontolerance forming analgesia with reduced side effects at the spinal level. DN-9 might be a promising compound for developing multifunctional opioid analgesics with limited adverse effects. Perspective: This article presents the potent and nontolerance forming analgesia effects of DN-9 in a series of preclinical pain models with less opioid related adverse effects at the spinal level in mice. This study also demonstrates that DN-9 has translational potential into an intrathecal analgesic.
Learn More >Opioids are frequently overprescribed after surgery. The 2018 American Urological Association position statement on opioid use suggests using the lowest dose and potency to achieve pain control, but a lack of procedure-specific prescribing guidelines contributes to wide variation in prescribing patterns. To address this gap, this study aims to develop opioid prescribing recommendations through an expert panel consensus.
Learn More >Transcutaneous electrical nerve stimulation (TENS) promotes antinociception by activating the descending pain modulation pathway and consequently releasing endogenous analgesic substances. In addition, recent studies have shown that the endocannabinoid system controls pain. Thus, the present study investigated the involvement of the endocannabinoid system in TENS-induced antinociception of cancer pain using a cancer pain model induced by intraplantar (i.pl.) injections of Ehrlich tumor cells in male Swiss mice. Low- and high-frequency TENS was applied for 20 min to the mice's paws, and to investigate the involvement of the endocannabinoid system were used the N-(peperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pitazole-3-carboixamide (AM251), a cannabinoid CB receptor antagonist and (5Z,8Z,11Z,14Z)-5,8,11,14-eicosatetraenyl-methylester phosphonofluoridic acid (MAFP), an inhibitor of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase, injected by via i.pl., intrathecal (i.t.), and intra-dorsolateral periaqueductal gray matter (i.dl.PAG). Furthermore, liquid chromatography-tandem mass spectrometry, western blot, and immunofluorescence assays were used to evaluate the endocannabinoid anandamide (AEA) levels, cannabinoid CB receptor protein levels, and cannabinoid CB receptor immunoreactivity, respectively. Low- and high-frequency TENS reduced the mechanical allodynia induced by Ehrlich tumor cells and this effect was reversed by AM251 and potentiated by MAFP at the peripheral and central levels. In addition, TENS increased the AEA levels and the cannabinoid CB receptor protein levels and immunoreactivity in the paw, spinal cord, and dorsolateral PAG. These results suggest that low- and high-frequency TENS is effective in controlling cancer pain, and the endocannabinoid system is involved in this effect at both the peripheral and central levels. Perspective: TENS is a non-pharmacological strategy that may be used to control cancer pain. Identification of a new mechanism involved in its analgesic effect could lead to the development of clinical studies as well as an increase in its application, lessening the need for pharmacological treatments.
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