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Since cloning and characterizing the first nociceptive ion channel Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1), other TRP channels involved in nociception have been cloned and characterized, which include TRP Vanilloid 2 (TRPV2), TRP Vanilloid 3 (TRPV3), TRP Vanilloid 4 (TRPV4), TRP Ankyrin 1 (TRPA1) and TRP Melastatin 8 (TRPM8), more recently TRP Canonical 1, 5, 6 (TRPC1, 5, 6), TRP Melastatin 2 (TRPM2) and TRP Melastatin 3 (TRPM3). These channels are predominantly expressed in C and Aδ nociceptors and transmit noxious thermal, mechanical and chemical sensitivities. TRP channels are modulated by pro-inflammatory mediators, neuropeptides and cytokines. Significant advances have been made targeting these receptors either by antagonists or agonists to treat painful conditions. In this review, we will discuss TRP channels as targets for next generation analgesics and the side effects that may ensue as a result of blocking/activating these receptors, because they are also involved in physiological functions such as release of vasoactive neuropeptides and regulation of vascular tone, maintenance of the body temperature, gastrointestinal motility, urinary bladder control, etc.
Male circumcision (MC) is one of the oldest and most common operations performed all over the world. It can be performed at different ages, using different surgical techniques, for different religious, cultural and medical reasons.Our aim is to examine and compare the various methods of analgesia and different surgical procedures reported in literature that are applied in infant MC. We performed a PubMed, MEDLINE, EMBASE and Cochrane search in the papers published since 2000: 14 studies met the inclusion criteria, most of them showing that a combined pharmacological and non-pharmacological intervention is the best analgesic option, in particular when the dorsal penile nerve block is combined with other treatments. The Mogen surgical procedure seems to be the less painful surgical intervention, when compared with Gomco clamp or PlastiBell device. Only 3 papers studied groups of at least 20 babies each with the use of validated pain scales. Data show a dramatic decrease of pain with dorsal penile nerve block, plus acetaminophen associated to oral sucrose or topic analgesic cream. However, no procedure has been found to definetively eliminate pain; the gold standard procedure to make MC totally painfree has not yet been established.
The objective of this study was to improve the patient comfort and safety during procedures done under anaesthesia and sedation. The analgesia nociception index (ANI) noninvasively provides information on the nociception-antinociception balance, and it can be used to assess analgesia objectively. We aimed to compare the effects of analgesia management with conventional methods and with ANI monitoring on total opioid consumption, sedation and analgesia levels in patients who underwent colonoscopy using sedo-analgesia.
Optogenetic tools enable cell selective and temporally precise control of neuronal activity; yet, difficulties in delivering sufficient light to the spinal cord of freely behaving animals have hampered the use of spinal optogenetic approaches to produce analgesia. We describe an epidural optic fiber designed for chronic spinal optogenetics that enables the precise delivery of light at multiple wavelengths to the spinal cord dorsal horn and sensory afferents.
Stress-induced analgesia (SIA) refers to a reduced pain response after stress exposure, which is mediated by descending pain-inhibitory circuits and may be an indicator of adequate centrally mediated pain control. We used functional magnetic resonance imaging to assess brain mechanisms of SIA in 21 healthy participants. Using a block design series of mildly painful pressure stimuli were applied to the left medial phalanx of the second digit during functional magnetic resonance imaging. Mental arithmetic combined with increasing levels of noise was used as a stressor. Verbal ratings, changes in blood pressure and heart rate confirmed the validity of the stress induction. Post-stress pain thresholds and pain tolerance were significantly higher and post-stress pain and unpleasantness ratings were significantly lower compared to pre-stress levels. SIA led to an increase of the blood-level-dependent oxygenation response in the primary somatosensory cortex, bilaterally in the anterior insula, and secondary somatosensory cortex. The increase in pain tolerance correlated significantly with activation in the rostral anterior cingulate cortex and pain unpleasantness with activation in the dorsal anterior cingulate cortex. SIA seems to activate similar brain networks as placebo analgesia or analgesia mediated by diffuse noxious inhibitory controls and involved sensory, affective and cognitive modulatory circuits.
The clinical efficacy of fentanyl for pain control differs greatly across individuals. The purpose of this study was to investigate the impact of CYP3A4*1G polymorphism including wild-type homozygote (CYP3A4*1/*1, GG), mutant heterozygote (CYP3A4*1/*1G, GA), and mutant homozygote (CYP3A4*1G/*1G, AA) on fentanyl analgesia in Chinese patients undergoing hysteroscopy by the assessment of analgesia nociception index (ANI).
Pain inhibition by additional somatosensory input is the rationale for the widespread use of Transcutaneous Electrical Nerve Stimulation (TENS) to relieve pain. Two main types of TENS produce analgesia in animal models: high-frequency (∼50-100 Hz) and low-intensity 'conventional' TENS, and low-frequency (∼2-4 Hz) and high-intensity 'acupuncture-like' TENS. However, TENS efficacy in human participants is debated, raising the question of whether the analgesic mechanisms identified in animal models are valid in humans. Here, we used a sham-controlled experimental design to clarify the efficacy and the neurobiological effects of 'conventional' and 'acupuncture-like' TENS in 80 human volunteers. To test the analgesic effect of TENS we recorded the perceptual and brain responses elicited by radiant heat laser pulses that activate selectively Aδ and C cutaneous nociceptors. To test whether TENS has a long-lasting effect on brain state we recorded spontaneous electrocortical oscillations. The analgesic effect of 'conventional' TENS was maximal when nociceptive stimuli were delivered homotopically, to the same hand that received the TENS. In contrast, 'acupuncture-like' TENS produced a spatially-diffuse analgesic effect, coupled with long-lasting changes both in the state of the primary sensorimotor cortex (S1/M1) and in the functional connectivity between S1/M1 and the medial prefrontal cortex, a core region in the descending pain inhibitory system. These results demonstrate that 'conventional' and 'acupuncture-like' TENS have different analgesic effects, which are mediated by different neurobiological mechanisms.
Cholesterol plays vital roles in many central physiological and pathological processes. As a key component in the cell membrane, cholesterol can regulate a variety of ion channels, including ligand-gated ion channels (LGICs). However, relatively little is known about the molecular detail and in vivo consequence of cholesterol-LGIC interaction. Here, we reveal that membrane cholesterol depletion significantly inhibits the potentiating effects of dehydroxylcannabidiol (DH-CBD) on glycine-activated currents (IGly) in HEK 293T cells expressing α1/α3 glycine receptors (GlyRs). Simvastatin considerably decreases cholesterol levels and DH-CBD-induced potentiation of IGly in the spinal cord of mice. Simvastatin also significantly decreases DH-CBD analgesia in acute and chronic pain of mice. The cholesterol levels in the dorsal horn of spinal cord, measured by mass spectrometry imaging, are specifically correlated with cannabinoid potentiation of spinal GlyRs and cannabinoid-induced analgesia. These findings suggest that spinal cholesterol is critical for the efficacy of glycinergic cannabinoid-induced analgesia.
Family-centered care aims to consider family preferences and values in care delivery. Our study examines parent decisions regarding anesthesia type (caudal regional block or local anesthesia) among a diverse sample of children undergoing urologic surgeries. Differences in anesthesia type were examined by known predictors of health disparities, including child race/ethnicity, parental English proficiency, and a proxy for household income.
Background Total knee replacement is often associated with significant postoperative pain. Although the use of a femoral nerve block is well-established, local infiltration analgesia has gained popularity in recent years. We compared single-shot local infiltration analgesia with a single-shot femoral nerve block for patients undergoing primary total knee arthroplasty. Methods A total of 194 patients were randomised to receive either local infiltration analgesia (150 ml bupivacaine 0.067% with adrenaline) or a femoral nerve block (20 ml 0.375% levobupivacaine). Both groups received spinal anaesthesia. The primary outcome measure was the total morphine consumption. Secondary outcome measures included: post-operative pain scores, rehabilitation goals, readiness for discharge, and physical, mental, and functional outcomes, including the Oxford Knee Score (OKS). Results A total of 69 patients in the local infiltration analgesia group and 79 patients in the femoral nerve block group were analysed. Median total morphine consumption was significantly greater in the local infiltration analgesia group as compared to the femoral nerve block group (54.67 mg vs 45 mg, respectively, p=0.0388). The post-operative OKS at six weeks was slightly more improved for the femoral nerve block group than for local infiltration analgesia (12.5 vs 9 point median improvements for the femoral nerve block and local infiltration analgesia groups, respectively, p=0.0261). There were no statistically significant differences in other secondary outcome measures. Conclusion A single-shot femoral nerve block significantly reduces the opioid requirement for primary total knee arthroplasty but is otherwise comparable to single-shot local infiltration analgesia.
The purpose of this study was to investigate the ability of chloroquine and chloroquine in combination with vasoconstrictor epinephrine to act as a local anesthetic in skin analgesia. After subcutaneous injection of drugs in rats, the inhibition of the cutaneous trunci muscle reflex (CTMR) is designed for evaluation of the cutaneous analgesic effect. The analgesic effect of chloroquine was compared with that of bupivacaine or coadministration of chloroquine and epinephrine. Chloroquine produced exactly the same local anesthesia as bupivacaine did in a dose-dependent manner. On the ED50 (50 % effective dose) basis, the analgesic potency was chloroquine (4.81 [4.45-5.20] μmol) < bupivacaine (0.46 [0.40‒0.52] μmol) (p < 0.01). At every equipotent dose tested (ED25, ED50 and ED75), chloroquine had a longer duration of cutaneous analgesia than bupivacaine (p < 0.01). Epinephrine enhanced the potency and duration of chloroquine-induced cutaneous analgesia. We found that chloroquine and bupivacaine elicit dose-dependent cutaneous analgesia. Chloroquine is not as potent as bupivacaine, but acts as an infiltrative anesthetic for a longer duration of time and is more potent and effective when used in combination with epinephrine.
Previous human imaging studies manipulating attention or expectancy have identified the periaqueductal gray (PAG) as a key brainstem structure implicated in endogenous analgesia. However, animal studies indicate that PAG analgesia is mediated largely via caudal brainstem structures, such as the rostral ventromedial medulla (RVM) and locus coeruleus (LC). To identify their involvement in endogenous analgesia, we used brainstem optimized, whole-brain imaging to record responses to concurrent thermal stimulation (left forearm) and visual attention tasks of titrated difficulty in 20 healthy subjects. The PAG, LC, and RVM were anatomically discriminated using a probabilistic atlas. Pain ratings disclosed the anticipated analgesic interaction between task difficulty and pain intensity (p < 0.001). Main effects of noxious thermal stimulation were observed across several brain regions, including operculoinsular, primary somatosensory, and cingulate cortices, whereas hard task difficulty was represented in anterior insular, parietal, and prefrontal cortices. Permutation testing within the brainstem nuclei revealed the following: main effects of task in dorsal PAG and right LC; and main effect of temperature in RVM and a task × temperature interaction in right LC. Intrasubject regression revealed a distributed network of supratentorial brain regions and the RVM whose activity was linearly related to pain intensity. Intersubject analgesia scores correlated to activity within a distinct region of the RVM alone. These results identify distinct roles for a brainstem triumvirate in attentional analgesia: with the PAG activated by attentional load; specific RVM regions showing pronociceptive and antinociceptive processes (in line with previous animal studies); and the LC showing lateralized activity during conflicting attentional demands.SIGNIFICANCE STATEMENT Attention modulates pain intensity, and human studies have identified roles for a network of forebrain structures plus the periaqueductal gray (PAG). Animal data indicate that the PAG acts via caudal brainstem structures to control nociception. We investigated this issue within an attentional analgesia paradigm with brainstem-optimized fMRI and analysis using a probabilistic brainstem atlas. We find pain intensity encoding in several forebrain structures, including the insula and attentional activation of the PAG. Discrete regions of the rostral ventromedial medulla bidirectionally influence pain perception, and locus coeruleus activity mirrors the interaction between attention and nociception. This approach has enabled the resolution of contributions from a hub of key brainstem structures to endogenous analgesia.
Chronic pain treatment remains a major challenge and pharmacological interventions are associated with important side effects. Manual medicine treatments such as massage, acupuncture, manipulation of the fascial system (MFS), and osteopathic manipulative treatments produce pain relief in humans, but the underlying mechanism is poorly understood limiting leverage and optimization of manual medicine techniques as safe pain therapy. To decipher the physiological mechanisms of manipulative medicine treatments, we have established a preclinical model. Here, we established a murine model of massage-like stroking (MLS)-induced analgesia. We characterized that the analgesia effects were present in both sexes, and were independent of the experimenters, handling, consciousness, and opioid receptors. MLS alleviates thermal pain in naive mice and postoperative pain hypersensitivity. This novel model will allow discovery of the physiological mechanisms involved in MLS-induced analgesia and identification of new therapeutic strategies.
The present study examined the contribution of expectations to analgesia induced by heterotopic noxious counter-stimulation (HNCS) in healthy volunteers assigned to a control group or 1 of 3 experimental groups in which expectations were either assessed (a priori expectations) or manipulated using suggestions (hyperalgesia and analgesia). Acute shock-pain, the nociceptive flexion reflex (RIII-reflex), and shock-related anxiety were measured in response to electrical stimulations of the right sural nerve in the baseline, HNCS, and recovery periods. Counter-stimulation was applied on the contralateral forearm using a flexible cold pack. A priori expectations were strongly associated with the actual magnitude of the analgesia induced by HNCS. In comparison to the control condition, suggestions of hyperalgesia led to an increase in RIII-reflex amplitude and shock-pain, while suggestions of analgesia resulted in a greater decrease in RIII-reflex amplitude, which confirms that the analgesic process normally activated by HNCS can be blocked or enhanced by the verbal induction of expectations through suggestions. Changes in shock-anxiety induced by these suggestions were correlated to changes in shock-pain and RIII-reflex, but these changes did not emerge as a mediator of the association between manipulated expectations and HNCS analgesia. Overall, the results demonstrate that HNCS analgesia is modulated by expectations, either from a priori beliefs or suggestions, and this appears to be independent of anxiety processes.
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