piperidines and Nociceptive-Pain

Opioids in general and remifentanil in particular can induce hyperalgesia. Preclinical data suggest that cannabidiol might have the capacity to reduce opioid-induced hyperalgesia (OIH). Thus, we investigated the effect of oral cannabidiol on OIH in healthy volunteers using an established pain model. Twenty-four healthy participants were included in this randomized, double-blinded, crossover study and received either a 1600-mg single-dose oral cannabidiol or placebo. Hyperalgesia, allodynia, and pain were induced by intracutaneous electrical stimulation. To provoke OIH, participants recieved an infusion of 0.1 µg/kg/min remifentanil over a time frame of 30 minutes, starting 100 minutes after oral cannabidiol ingestion. The primary outcome was the area of hyperalgesia (in square centimetres) up to 60 minutes after remifentanil administration. The area of allodynia (in square centimetres) and pain (numeric rating scale) were also assessed.Cannabidiol had no significant effect on hyperalgesia, allodynia, or pain at any time point of measurement compared with placebo. The area of hyperalgesia after remifentanil administration significantly increased compared with baseline (17.0 cm 2 [8.1-28.7] vs 25.3 cm 2 [15.1-39.6]; P = 0.013). Mean cannabidiol blood levels were 4.1 ± 3.0 µg/L (mean ± SD) at 130 minutes after ingestion and were 8.2 μg/L ± 6.9 µg/L (mean ± SD) at 200 minutes. Cannabidiol was well tolerated. We conclude that a high single-oral dose of 1600-mg cannabidiol is not effective in reducing OIH. Before excluding an effect of cannabidiol on OIH, research should focus on drug formulations enabling higher cannabidiol concentrations.

Topics: Acute Pain; Adult; Analgesics, Opioid; Cannabidiol; Cross-Over Studies; Double-Blind Method; Humans; Hyperalgesia; Nociceptive Pain; Piperidines; Remifentanil

To evaluate the efficacy of reflex entropy (RE)/state entropy (SE) in monitoring the response to nociceptive stimulus during propofol-remifentanil infusion.. After the approval of the hospital ethics committee, sixty American Society of Anesthesiologists (ASA) classification 1-2 patients, aged 18-65 years, receiving the hypogastrium operation undergoing general anesthesia, were randomly allocated to groups A and B with different remifentanil concentrations. After the concentration of propofol and remifentanil reached balance, tetanic stimulation, intubation, and incision were performed respectively with certain intervals. RE and SE were monitored during this procedure.. Twelve patients were withdrawn from this study due to the use of vasoactive drugs. Finally, there were 28 cases in group A and 20 cases in group B. The RE and SE were not significantly changed before and after the tetanic stimulation in both groups (all P>0.05). Both RE and SE were significantly increased after intubation in group B (both P<0.05) and after skin incision in both groups (all P<0.05). Under the same stimulation, RE and SE showed no significant difference among groups administered with different levels of remifentanil (P>0.05).. Under the anesthesia with propofol+remifentanil, nociceptive response may cause the increase of RE and SE. Therefore, RE and SE may be useful parameters for monitoring the nociceptive response during general anaesthesia.

Topics: Adolescent; Adult; Anesthesia, General; Electroencephalography; Entropy; Feasibility Studies; Female; Humans; Middle Aged; Monitoring, Intraoperative; Nociceptive Pain; Physical Stimulation; Piperidines; Propofol; Remifentanil; Young Adult

Whether pinocembrin (PCN) could be used to alleviate hip fracture-induced pain is investigated in this research. Aged rats with hip fractures were treated with vehicle or 80 mg/kg/day PCN from

Topics: Aging; Animals; Disease Models, Animal; Flavanones; Hip Fractures; Indoles; Male; Neurokinin-1 Receptor Antagonists; Nociceptive Pain; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Signal Transduction; Substance P

This study investigated the role of NR2B in a modulated pain process in the painful diabetic neuropathy (PDN) rat using various pain stimuli.. DM rats showed a significant reduction in pain threshold in response to the tactile and thermal stimuli and higher nociceptive response during the formalin test accompanied by the higher expression of phosphorylated spinal NR2B in both sides of the spinal cord. Ifenprodil treatment for both doses showed anti-allodynic and anti-nociceptive effects with lower expression of phosphorylated and total spinal NR2B.. We suggest that the pain process in the streptozotocin-induced diabetic rat that has been modulated is associated with the higher phosphorylation of the spinal NR2B expression in the development of PDN, which is similar to other models of neuropathic rats.

Topics: Analgesics; Animals; Behavior, Animal; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Hyperalgesia; Male; Nociceptive Pain; Nociceptors; Pain Measurement; Phosphorylation; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Streptozocin

NLX-112 (a.k.a. befiradol, F13640) is a drug candidate intended for the treatment of l-DOPA-induced dyskinesia. It is a highly selective serotonin 5-HT. The activity of NLX-112 was tested in mouse models of acute pain (hot plate), tonic pain (intraplantar formalin test), in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy and in the streptozotocin (STZ)-induced model of painful diabetic neuropathy.. NLX-112 may have significant potential for treatment of tonic pain but may be less promising as a candidate for treatment of chemotherapy-induced or diabetic neuropathic pain.

Topics: Analgesics; Animals; Antineoplastic Agents; Cyclohexanes; Diabetic Neuropathies; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Hot Temperature; Hyperalgesia; Male; Mice; Motor Activity; Neuralgia; Nociceptive Pain; Organoplatinum Compounds; Oxaliplatin; Piperazines; Piperidines; Pyridines; Random Allocation; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Streptozocin; Touch

This study evaluated the influence of the pre-treatment with AM251 (a cannabinoid type I receptor (CB1) selective antagonist) on the stress-induced antinociception promoted by restraint in the fish Leporinus macrocephalus. The application of 3 and 5 min of restraint stress promoted an inhibition of the behavioural response to the subcutaneous injection of 3% formaldehyde (increase in locomotor activity), suggesting the activation of an antinociceptive system. The acute intraperitoneal administration of AM251 (3 mg·kg(-1)) impaired this antinociceptive response induced by 3 and 5 min of restraint stress. The fish treated with AM251 before the application of restraint stress presented an increase in locomotor activity after the subcutaneous injection of formaldehyde, similar to fish not exposed to restraint, suggesting that the stress-induced antinociception promoted by restraint in fish is probably mediated by cannabinoid CB1 receptors. The results presented in this paper suggest the participation of the endocannabinoid system in nociception modulation in fish, supporting the hypothesis that an endogenous antinociceptive system activated by restraint stress is present in fish and that the modulation of antinociception by the CB1 receptor is evolutionary well-conserved across vertebrates.

Topics: Animal Fins; Animals; Cannabinoid Receptor Antagonists; Fish Proteins; Fishes; Formaldehyde; Motor Activity; Nociceptive Pain; Pain Measurement; Pain Perception; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Restraint, Physical; Stress, Psychological; Time Factors

Neurosurgery often requires skull immobilization with a Mayfield clamp, which often causes brief intense nociceptive stimulation, hypertension and tachycardia. Blunting this response may help prevent increased intracranial pressure, cerebral aneurysm or vascular malformation rupture, and/or myocardial stress. While various interventions have been described to blunt this response, no reports have compared administration of a propofol versus a remifentanil bolus.. We retrospectively analyzed the hemodynamic response to Mayfield placement in over 800 patients who received a prior propofol or remifentanil bolus from 2004 to 2010.. Patients who received remifentanil experienced a 55% smaller increase in heart rate (p < 0.0001) and a 40% smaller increase in systolic blood pressure (p < 0.0001) after Mayfield placement than patients who received propofol. These data were retrospectively obtained from patients who were not randomized to receive remifentanil versus propofol, and hence these data could be subject to possible confounding. Nonetheless, these differences remained significant after multivariate analysis for possible confounding variables.. Thus, a remifentanil bolus is more effective than a propofol bolus in blunting hemodynamic responses to Mayfield placement, and possibly for other short, intense nociceptive stimuli.

Topics: Anesthetics, Intravenous; Blood Pressure; Female; Heart Rate; Hemodynamics; Humans; Intracranial Aneurysm; Intracranial Pressure; Male; Middle Aged; Neurosurgical Procedures; Nociceptive Pain; Piperidines; Propofol; Remifentanil; Restraint, Physical; Retrospective Studies; Skull

Acute and chronic pain resulting from injury, surgery, or disease afflicts >100 million Americans each year, having a severe impact on mood, mental health, and quality of life. The lack of structural and functional information for most ion channels, many of which play key roles in the detection and transmission of noxious stimuli, means that there remain unidentified therapeutic targets for pain management. This study focuses on the transient receptor potential canonical subfamily 4 (TRPC4) ion channel, which is involved in the tissue-specific and stimulus-dependent regulation of intracellular Ca²⁺ signaling. Rats with a transposon-mediated TRPC4-knockout mutation displayed tolerance to visceral pain induced by colonic mustard oil (MO) exposure, but not somatic or neuropathic pain stimuli. Moreover, wild-type rats treated with a selective TRPC4 antagonist (ML-204) prior to MO exposure mimicked the behavioral responses observed in TRPC4-knockout rats. Significantly, ML-204 inhibited visceral pain-related behavior in a dose-dependent manner without noticeable adverse effects. These data provide evidence that TRPC4 is required for detection and/or transmission of colonic MO visceral pain sensation. In the future, inhibitors of TRPC4 signaling may provide a highly promising path for the development of first-in-class therapeutics for this visceral pain, which may have fewer side effects and less addictive potential than opioid derivatives.

Topics: Analgesics; Animals; Colon; Dose-Response Relationship, Drug; Female; Gene Knockout Techniques; Indoles; Male; Mustard Plant; Neuralgia; Nociception; Nociceptive Pain; Piperidines; Plant Oils; Rats; Rats, Inbred F344; Rats, Transgenic; RNA, Messenger; TRPC Cation Channels; Visceral Pain

The discovery and synthesis of a new series of pyrimidines as potent sigma-1 receptor (σ1R) antagonists, associated with pharmacological antineuropathic pain activity, are the focus of this article. The new compounds were evaluated in vitro in σ-1 and σ-2 receptor binding assays. The nature of the pyrimidine scaffold was crucial for activity, and a basic amine was shown to be necessary according to the known pharmacophoric model. The most promising derivative was 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine (137), which exhibited a high binding affinity to σ1R receptor (Ki σ1 = 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivo tests, compound 137 exerted dose-dependent antinociceptive effects in mice formalin model and rats CCI models of neuropathic pain. In addition, no motor impairments were found in rotarod tests; acceptable pharmacokinetic properties were also noted. These data suggest compound 137 may constitute a novel class of drugs for the treatment of neuropathic pain.

Topics: Animals; Behavior, Animal; Carbon Tetrachloride; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Mice; Molecular Structure; Motor Activity; Neuralgia; Neuroprotective Agents; Nociceptive Pain; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor; Structure-Activity Relationship

Nocistatin (NST) and Nociceptin/Orphanin FQ (N/OFQ) are derived from the same precursor protein, pre-proN/OFQ, and exert opposite effects on the modulation of pain signals. However, the role of the peripheral N/OFQ and the NOP receptor, which is located at the endings of sensory nerves, in inflammatory pain was not ascertained. NST administered intrathecally (i.t.) prevented the nociceptive effects induced by i.t. N/OFQ and PGE₂. Moreover an up regulation of N/OFQ was shown in the rat in response to peripheral inflammation. Here, we investigated the effects of intraplantar (i.pl.) administration of functional N/OFQ and NOP receptor antagonists in a rat model of inflammatory pain. Our findings showed that i.pl. injection of (±)-J 113397, a selective antagonist of the NOP receptor, and NST, the functional N/OFQ antagonist, prior to carrageenan significantly reduced the paw allodynic and thermal hyperalgesic threshold induced by the inflammatory agent. The resulting antiallodynic and antihyperalgesic effects by co-administering NST and (±)-J 113397 prior to carrageenan were markedly enhanced, and the basal latencies were restored. Thus, it is likely that the peripheral N/OFQ/NOP receptor system contributes to the abnormal pain sensitivity in an inflammatory state.

Topics: Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Benzimidazoles; Disease Models, Animal; Drug Therapy, Combination; Hyperalgesia; Inflammation; Injections, Subcutaneous; Male; Metatarsus; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Nociceptive Pain; Opioid Peptides; Pain Threshold; Peripheral Nerves; Piperidines; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Signal Transduction

Painful stimuli activate nociceptive C fibers and induce synaptic long-term potentiation (LTP) at their spinal terminals. LTP at C-fiber synapses represents a cellular model for pain amplification (hyperalgesia) and for a memory trace of pain. μ-Opioid receptor agonists exert a powerful but reversible depression at C-fiber synapses that renders the continuous application of low opioid doses the gold standard in pain therapy. We discovered that brief application of a high opioid dose reversed various forms of activity-dependent LTP at C-fiber synapses. Depotentiation involved Ca(2+)-dependent signaling and normalization of the phosphorylation state of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This also reversed hyperalgesia in behaving animals. Opioids thus not only temporarily dampen pain but may also erase a spinal memory trace of pain.

Topics: Analgesics, Opioid; Animals; Calcium Signaling; Evoked Potentials; Hyperalgesia; Long-Term Potentiation; Male; Naloxone; Nerve Fibers, Unmyelinated; Nociceptive Pain; Phosphorylation; Piperidines; Protein Kinase C; Protein Phosphatase 1; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Opioid, mu; Remifentanil; Sciatic Nerve; Somatostatin; Spinal Cord; Synapses