Pain
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Protein interacting with C kinase 1 (PICK1) is a PDZ-containing protein that binds to AMPA receptor (AMPAR) GluR2 subunit and protein kinase Cα (PKCα) in the central neurons. It functions as a targeting and transport protein, presents the activated form of PKCα to synaptic GluR2, and participates in synaptic AMPAR trafficking in the nervous system. Thus, PICK1 might be involved in many physiological and pathological processes triggered via the activation of AMPARs. ⋯ Injection of CFA into a hind paw, but not a hind paw incision, increased PKCα-mediated GluR2 phosphorylation at Ser880 and GluR2 internalization in dorsal horn. These increases were absent when spinal cord PICK1 was deficient. Given that dorsal horn PKCα-mediated GluR2 phosphorylation at Ser880 and GluR2 internalization contribute to the maintenance of CFA-induced inflammatory pain, our findings suggest that spinal PICK1 may participate in the maintenance of persistent inflammatory pain, but not in incision-induced post-operative pain, through promoting PKCα-mediated GluR2 phosphorylation and internalization in dorsal horn neurons.
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Tolerance to morphine-induced analgesia is an intractable phenomenon, often hindering its prolonged applications in the clinics. The enhanced pronociceptive actions of spinal pain-related molecules such as calcitonin gene-related peptide (CGRP) may underlie this phenomenon and could be a promising target for intervention. We demonstrate here how CGRP regulates the development of morphine analgesic tolerance at the spinal level. ⋯ Chronic morphine-induced behavioural responses and biochemical events were all subjugated to modulation by disrupting CGRP receptor signaling. Together, these data suggest that CGRP contributes to the development of tolerance to morphine-induced analgesia by regulating the activation of the neuronal CaMKII-CREB, microglial p38-NFκB and astroglial ERK-Stat1/3 cascades. Targeting CGRP-associated signaling molecules may prolong or restore morphine's analgesic properties upon a chronic exposure.
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Review Meta Analysis
Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies.
Although a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the available literature on sex differences in μ and mixed μ/κ opioid effect on acute and experimental pain. Fifty unique studies (including three unpublished studies) were included in the analyses. ⋯ Female patients had greater μ/κ opioid analgesia (n=7, effect size 0.84; 95% c.i. 0.25-1.43, P=0.005), but no sex-analgesia association was present in experimental studies (n=7). Sex differences exist in morphine-induced analgesia in both experimental pain studies and clinical PCA studies, with greater morphine efficacy in women. The data on non-morphine μ and mixed μ/κ-opioids are less convincing and require further study.
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Randomized Controlled Trial Clinical Trial
Predicting the analgesic effect to oxycodone by 'static' and 'dynamic' quantitative sensory testing in healthy subjects.
The large inter-individual variability in the magnitude of analgesia in response to opioids and the high prevalence of adverse events associated with their use underline the clinical importance of being able to predict who will or will not respond to opioid treatment. The present study used both static and dynamic quantitative sensory testing (QST) on 40 healthy volunteers in order to test whether this methodology can predict the analgesic effects of oral oxycodone, as compared to a placebo, on latency to onset, pain intensity, and tolerance to the cold pressor test (CPT). Static QST consisted of measuring heat and cold pain thresholds. ⋯ The static QST results showed that heat pain thresholds predicted the magnitude of reduction in pain intensity in response to oxycodone treatment (F((1,22))=5.63, p=0.027, R(2)=0.17). The dynamic QST results showed that TS predicted the effect of oxycodone on the tolerance to CPT (F((1,38))=9.11, p=0.005, R(2)=0.17). These results suggest that both static and dynamic QST have the potential to be useful in the prediction of the response to opioid treatment.
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Randomized Controlled Trial Clinical Trial
Deciphering the role of endogenous opioids in high-frequency TENS using low and high doses of naloxone.
Previous human studies have shown that the analgesic effect of high-frequency TENS could not be reversed by low doses of naloxone. The aim of the present study was to reinvestigate the possible contribution of opioid receptors to high-frequency TENS analgesia by using low (0.02 mg/kg) and high (0.14 mg/kg) doses of naloxone. Naloxone (high and low doses) and saline were administered intravenously to young healthy adults using a triple-blind randomized cross-over design. ⋯ However, when a high dose of naloxone was administered, TENS analgesia was completely blocked (p=.20). These results suggest that high-frequency TENS involves opioid receptors. An insufficient amount of opioid antagonist likely prevented previous human studies from discovering the importance of opioid receptors in producing high-frequency TENS analgesia.