Acute Noxious Stimulus Research Articles

Enhanced Activation Of The Parabrachial Nucleus Following An Acute Noxious Stimulus Is Observed In Male And Female Mice With Osteoarthritis

Enhanced Activation Of The Parabrachial Nucleus Following An Acute Noxious Stimulus Is Observed In Male And Female Mice With Osteoarthritis

Assessment of Monoacyglycerol Lipase Inhibition for Acute and Chronic Antinociception in a Behavioral Battery for Testing Candidate Analgesics in Mice

Objective and Hypothesis There is a pressing need for discovery of novel, safe, and effective analgesics with improved preclinical-to-clinical translation. This study addressed these issues by evaluating the antinociceptive effectiveness of the monoacylglycerol lipase (MAGL)-selective inhibitors MJN110 and JZL184 in a battery of pain-stimulated, pain-depressed, and pain-independent behaviors in male and female mice. Ketoprofen (cyclooxygenase1/2 inhibitor) was used as a clinically-effective analgesic positive control, and ∆9-tetrahydrocannabinol (THC; cannabinoid 1/2 receptor (CB1/2­R) agonist) as a negative control that is not clinically effective to treat acute pain. We hypothesized that ketoprofen and MAGL-selective inhibitors would produce antinociception on endpoints of pain-stimulated and pain-depressed behaviors at doses that did not alter pain-independent behaviors, whereas THC would not. Methods Intraperitoneal dilute lactic acid (IP acid) served as an acute noxious stimulus in male and female ICR mice to produce two IP acid-stimulated behaviors (stretching and facial grimace) and two IP acid-depressed behaviors (rearing and nesting). Pain-independent drug effects were assessed in nesting and locomotion in the absence of IP acid. All test drugs were delivered subcutaneously and evaluated for effectiveness to alleviate pain-related behaviors at doses below those that altered pain-independent behaviors. The assay of IP acid-depressed nesting was also used to assess MJN110 time course, sensitivity to blockade by the CB1R- and CB2R-selective antagonists rimonabant and SR144528, and effects of repeated dosing for 7 consecutive days. Results and Significance Ketoprofen (0.1-10 mg/kg) produced robust antinociception without general behavioral disruption on all IP acid-stimulated and IP acid-depressed behaviors. MJN110 (0.1-3.2 mg/kg) and JZL184 (1.0-32 mg/kg) produced antinociception without motor disruption on endpoints of stretching (MJN110 only), grimace, and nesting, but not rearing. THC (1-10 mg/kg) attenuated IP acid-stimulated stretching and facial grimace at doses that did not produce general motor disruption; however, THC did not alleviate IP acid-induced depression of either nesting or rearing. MJN110 (1.0 mg/kg) antinociception in the assay of IP acid-induced nesting depression showed a long duration (40min – 6hr) mediated by CB1R but not CB2R and tended to be stronger in females. Chronic MJN110 (1.0 mg/kg/day × 7 days) showed sex-dependent antinociception and tolerance, with females showing tolerance by Day 7 and males showing no significant antinociceptive effect across all 7 days. These results provide modest support for further consideration of MAGL-selective inhibitors, especially MJN110, as candidate analgesics, with future work needed to assess sex-dependent effects. However, it should be noted that none of the cannabinoids were as effective in this behavioral battery as ketoprofen.

Effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 on pain-depressed behavior in rats: comparison with ketorolac and diazepam.

This study examined effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 in an assay of pain-related behavioral depression. Adult, male Sprague-Dawley rats responded for electrical brain stimulation in a frequency-rate intracranial self-stimulation (ICSS) procedure. Intraperitoneal injection of 1.8% lactic acid served as an acute noxious stimulus to depress ICSS. Effects of KRM-II-81 were evaluated in the absence and presence of the acid noxious stimulus. The NSAID ketorolac and the benzodiazepine diazepam were tested as comparators. Neither ketorolac nor KRM-II-81 altered ICSS in the absence of the acid noxious stimulus; however, diazepam produced facilitation consistent with its abuse liability. Ketorolac blocked acid-induced depression of ICSS, and effects of 1.0 mg/kg ketorolac lasted for at least 5 h. KRM-II-81 (1.0 mg/kg) produced significant antinociception after 30 min that dissipated by 60 min. Diazepam also attenuated acid-depressed ICSS, but only at doses that facilitated ICSS when administered alone. The lack of ketorolac or KRM-II-81 effects on ICSS in the absence of the acid noxious stimulus suggests low abuse liability for both compounds. The effectiveness of ketorolac to block acid-induced ICSS depression agrees with clinical analgesic efficacy of ketorolac. KRM-II-81 produced significant but less consistent and shorter-acting antinociception than ketorolac.

Comparison of Reinforcing and Antinociceptive Effects of Agonists with Mixed NOP and MOP Receptor Agonist Action in Nonhuman Primates

Agonists with mixed nociceptin/orphanin FQ peptide (NOP) and mu opioid peptide (MOP) receptor agonist activities have been demonstrated as effective analgesics with fewer side effects. However, these newly developed compounds with different efficacies at the NOP and MOP receptors have not been compared in terms of their reinforcing and antinociceptive effects. The aim of this study was to determine and compare effects of AT‐121 and BU08028 (NOP/MOP partial agonists), AT‐175 (NOP full/MOP partial agonist), and cebranopadol (mixed NOP and opioid full agonist) in a series of behavioral assays established in rhesus monkeys (Macaca mutatta). Following systemic administration, AT‐121 (3–30 ug/kg), BU08028 (1–10 ug/kg), AT‐175 (1–10 ug/kg), and cebranopadol (1–5.6 ug/kg) all dose‐dependently produced antinociceptive effects against an acute noxious stimulus and attenuated capsaicin‐induced hypersensitivity. In the intravenous drug self‐administration assay, the relative reinforcing strengths (i.e., abuse potential) of these compounds were compared in monkeys under a progressive‐ratio schedule of reinforcement over a wide dose range. Unlike oxycodone and heroin producing robust reinforcing effects, AT‐121, BU08028, and AT‐175 did not significantly produce reinforcing effects. However, cebranopadol produced moderate reinforcing effects as compared to oxycodone and heroin. Taken together, these pharmacological studies in primates indicate that agonists with mixed NOP and MOP receptor agonist activities exert opioid‐like analgesic effects. Although the NOP receptor activation could attenuate the reinforcing effects mediated MOP partial agonist action, the NOP full agonist activity may not be able to completely attenuate the reinforcing effects mediated by MOP full agonist activity in primates.Support or Funding InformationThe US. NIH/NIDA grants (DA023281, DA027811, DA032568, and DA035359) and US. Department of Defense (W81XWH‐13‐2‐0045).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Optimising neonatal fMRI data analysis: Design and validation of an extended dHCP preprocessing pipeline to characterise noxious-evoked brain activity in infants

The infant brain is unlike the adult brain, with considerable differences in morphological, neurodynamic, and haemodynamic features. As the majority of current MRI analysis tools were designed for use in adults, a primary objective of the Developing Human Connectome Project (dHCP) is to develop optimised methodological pipelines for the analysis of neonatal structural, resting state, and diffusion MRI data. Here, in an independent neonatal dataset we have extended and optimised the dHCP fMRI preprocessing pipeline for the analysis of stimulus-response fMRI data. We describe and validate this extended dHCP fMRI preprocessing pipeline to analyse changes in brain activity evoked following an acute noxious stimulus applied to the infant's foot. We compare the results obtained from this extended dHCP pipeline to results obtained from a typical FSL FEAT-based analysis pipeline, evaluating the pipelines' outputs using a wide range of tests. We demonstrate that a substantial increase in spatial specificity and sensitivity to signal can be attained with a bespoke neonatal preprocessing pipeline through optimised motion and distortion correction, ICA-based denoising, and haemodynamic modelling. The improved sensitivity and specificity, made possible with this extended dHCP pipeline, will be paramount in making further progress in our understanding of the development of sensory processing in the infant brain.

Reinforcing, Antinociceptive, and Pruritic Effects of a G Protein‐Biased Mu Opioid Receptor Agonist, PZM21, in Primates

PZM21 is a newly discovered G protein‐biased mu opioid peptide (MOP) receptor agonist which exerts antinociceptive effects with fewer side effects in rodents. The aim of this study was to determine the functional profile of systemic and spinal delivery of PZM21 in non‐human primates. Effects of PZM21 were compared with those of MOP agonists, such as oxycodone and morphine, in a series of behavioral assays established in rhesus monkeys (Macaca mutatta). Following systemic administration, PZM21 (1–6 mg/kg) and oxycodone (0.1–0.6 mg/kg) dose‐dependently produced antinociceptive effects against an acute noxious stimulus. Similar to a prescription opioid oxycodone, PZM21 produced reinforcing effects in primates under fixed ratio (FR30) and progressive‐ratio (PR) schedules of intravenous drug self‐administration. Following intrathecal administration, PZM21 (0.03–0.3 mg) and morphine (0.003–0.03 mg) dose‐dependently produced antinociceptive effects. Although intrathecal PZM21 has a slower onset for eliciting itch scratching activities, intrathecal PZM21 (0.3 mg) and morphine (0.03 mg) both elicited robust scratching responses lasting for more than 5 hours. In addition, intrathecal PZM21 (0.03–0.3 mg) dose‐dependently attenuated capsaicin‐induced thermal allodynia. Anti‐allodynic effects of intrathecal PZM21 or morphine could be blocked by a MOP receptor antagonist, naltrexone. Taken together, these pharmacological studies in primates indicate that PZM21 displays similar functional efficacy as an analgesic like clinically used MOP agonists, oxycodone and morphine. Although structure‐based discovery of PZM21 opens a new, exciting chapter for G protein‐biased MOP agonists, the abuse potential and pruritic effect of PZM21 are not significantly different from those of clinically used opioid analgesics in primates.Support or Funding InformationThe US‐PHS grants DA044775, DA032568, and DA040693.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Relief of Pain-Depressed Behavior in Rats by Activation of D1-Like Dopamine Receptors

Clinically significant pain often includes a decrease in both behavior and mesolimbic dopamine signaling. Indirect and/or direct dopamine receptor agonists may alleviate pain-related behavioral depression. To test this hypothesis, the present study compared effects of indirect and direct dopamine agonists in a preclinical assay of pain-depressed operant responding. Male Sprague-Dawley rats with chronic indwelling microelectrodes in the medial forebrain bundle were trained in an intracranial self-stimulation (ICSS) procedure to press a lever for pulses of electrical brain stimulation. Intraperitoneal injection of dilute lactic acid served as an acute noxious stimulus to depress ICSS. Intraperitoneal lactic acid-induced depression of ICSS was dose-dependently blocked by the dopamine transporter inhibitor methylphenidate and the D1-selective agonist SKF82958, but not by the D2/3-selective agonists quinpirole, pramipexole, or sumanirole. The antinociceptive effects of methylphenidate and SKF82958 were blocked by the D1-selective antagonist SCH39166. Acid-induced stimulation of a stretching response was evaluated in separate groups of rats, but all agonists decreased acid-stimulated stretching, and antagonism experiments were inconclusive due to direct effects of the antagonists when administered alone. Taken together, these results suggest that D1-receptor stimulation is both sufficient to block acid-induced depression of ICSS and necessary for methylphenidate antinociception in this procedure. Conversely, D2/3-receptor stimulation is not sufficient to relieve pain-depressed behavior. These results support the hypothesis that pain-related depression of dopamine D1 receptor signaling contributes to pain-related depression of behavior in rats. Additionally, these results support further consideration of indirect dopamine agonists and direct D1 receptor agonists as candidate treatments for pain-related behavioral depression.

Experimental Muscle Pain Impairs the Synergistic Modular Control of Neck Muscles.

A motor task can be performed via different patterns of muscle activation that show regularities that can be factorized in combinations of a reduced number of muscle groupings (also referred to as motor modules, or muscle synergies). In this study we evaluate whether an acute noxious stimulus induces a change in the way motor modules are combined to generate movement by neck muscles. The neck region was selected as it is a region with potentially high muscular redundancy. We used the motor modules framework to assess the redistribution of muscular activity of 12 muscles (6 per side) in the neck region of 8 healthy individuals engaged in a head and neck aiming task, in non-painful conditions (baseline, isotonic saline injection, post pain) and after the injection of hypertonic saline into the right splenius capitis muscle. The kinematics of the task was similar in the painful and control conditions. A general decrease of activity was noted for the injected muscle during the painful condition together with an increase or decrease of the activity of the other muscles. Subjects did not adopt shared control strategies (motor modules inter subject similarity at baseline 0.73±0.14); the motor modules recorded during the painful condition could not be used to reconstruct the activation patterns of the control conditions, and the painful stimulus triggered a subject-specific redistribution of muscular activation (i.e., in some subjects the activity of a given muscle increased, whereas in other subjects it decreased with pain). Alterations of afferent input (i.e., painful stimulus) influenced motor control at a multi muscular level, but not kinematic output. These findings provide new insights into the motor adaptation to pain.

Effects of nicotinic acetylcholine receptor agonists in assays of acute pain-stimulated and pain-depressed behaviors in rats.

Agonists at nicotinic acetylcholine receptors (nAChRs) constitute one drug class being evaluated as candidate analgesics. Previous preclinical studies have implicated α4β2 and α7 nAChRs as potential mediators of the antinociceptive effects of (–)-nicotine hydrogen tartrate (nicotine) and other nAChR agonists; however, these studies have relied exclusively on measures of pain-stimulated behavior, which can be defined as behaviors that increase in frequency, rate, or intensity after presentation of a noxious stimulus. Pain is also associated with depression of many behaviors, and drug effects can differ in assays of pain-stimulated versus pain-depressed behavior. Accordingly, this study compared the effects of nicotine, the selective α4/6β2 agonist 5-(123I)iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), and the selective α7 agonist N-(3R)-1-azabicyclo(2.2.2)oct-3-yl-4-chlorobenzamide in assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats. Intraperitoneal injection of dilute lactic acid served as an acute noxious stimulus to either stimulate a stretching response or depress the operant responding, which is maintained by electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. Nicotine produced a dose-dependent, time-dependent, and mecamylamine-reversible blockade of both acid-stimulated stretching and acid-induced depression of ICSS. 5-I-A-85380 also blocked both acid-stimulated stretching and acid-induced depression of ICSS, whereas N-(3R)-1-azabicyclo(2.2.2)oct-3-yl-4-chlorobenzamide produced no effect in either procedure. Both nicotine and 5-I-A-85380 were ≥10-fold more potent in blocking the acid-induced depression of ICSS than in blocking the acid-induced stimulation of stretching. These results suggest that stimulation of α4β2 and/or α6β2 nAChRs may be especially effective to alleviate the signs of pain-related behavioral depression in rats; however, nonselective behavioral effects may contribute to apparent antinociception.

Effects of μ-opioid receptor agonists in assays of acute pain-stimulated and pain-depressed behavior in male rats: role of μ-agonist efficacy and noxious stimulus intensity.

Pain is associated with stimulation of some behaviors and depression of others, and μ-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six μ-agonists that varied in efficacy at μ-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All μ-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All μ-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy μ-agonist nalbuphine, but not the high-efficacy μ-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective μ-opioid analgesics and reveal distinctions between opioids based on efficacy at the μ-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs.

N-Methyl-d-Aspartate Receptor Agonism and Antagonism Within the Amygdaloid Central Nucleus Suppresses Pain Affect: Differential Contribution of the Ventrolateral Periaqueductal Gray

The amygdala contributes to the generation of pain affect, and the amygdaloid central nucleus (CeA) receives nociceptive input that is mediated by glutamatergic neurotransmission. The present study compared the contribution of N-methyl-d-aspartate (NMDA) receptor agonism and antagonism in the CeA to generation of the affective response of rats to an acute noxious stimulus. Vocalizations that occur following a brief tail shock (vocalization afterdischarges) are a validated rodent model of pain affect and were preferentially suppressed, in a dose-dependent manner, by bilateral injection into the CeA of NMDA (.1, .25, .5, or 1 μg/side) or the NMDA receptor antagonist d-(–)-2-amino-5-phosphopentanoic acid (AP5; 1, 2, or 4 μg/side). Vocalizations that occur during tail shock were suppressed to a lesser degree, whereas spinal motor reflexes (tail flick and hind limb movements) were unaffected by injection of NMDA or AP5 into the CeA. Injection of NMDA, but not AP5, into the CeA increased c-Fos immunoreactivity in the ventrolateral periaqueductal gray, and unilateral injection of the μ-opiate receptor antagonist H-d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; .25 μg) into ventrolateral periaqueductal gray prevented the antinociception generated by injection of NMDA into the CeA. These findings demonstrate that although NMDA receptor agonism and antagonism in the CeA produce similar suppression of pain behaviors, they do so via different neurobiologic mechanisms. PerspectiveThe amygdala contributes to production of the emotional dimension of pain. NMDA receptor agonism and antagonism within the CeA suppressed rats' emotional response to acute painful stimulation. Understanding the neurobiology underlying emotional responses to pain will provide insights into new treatments for pain and its associated affective disorders.

Does Stress within a Muscle Change in Response to an Acute Noxious Stimulus?

BackgroundAltered muscle activation during pain is thought to redistribute stress within muscles and ultimately decrease the load on painful structures. However, change in muscle stress during pain has not been directly tested. The aim of the present study is to determine whether stress within muscle tissue is reduced during local acute experimental pain.Methods and ResultsTen participants attended 2 experimental sessions that each involved isometric knee extension tasks in 2 series of control trials and 1 series of test trials at ∼10%MVC. Shear elastic modulus was measured from vastus lateralis using a shear wave elastographic technique (Supersonic Shear Imaging). Prior to the test contractions, a bolus of hypertonic (Pain) or isotonic saline (No-pain) was injected into vastus lateralis. Pain intensity was 5.2±1.0 during the painful contractions. The intra-session repeatability of the shear elastic modulus determined between control trials was good (ICC: 0.95 and 0.99; SEM: 5.1 and 9.3 kPa for No-pain and Pain, respectively). Muscle shear elastic modulus did not change systematically during Pain or No-pain contractions (all main effects and interaction P>0.14). Examination of data for individual participants showed that stress either increased or decreased. If the absolute change in modulus is considered between the control and the test trials, the change during Pain (16.2±9.5 kPa) was double that observed with No pain (7.9±5.9 kPa; P = 0.046).ConclusionThis is the first study to directly determine the change in stress within a muscle (change in shear elastic modulus) during pain. We conclude that experimental pain induced by hypertonic saline does not induce a systematic reduction in muscle stress during a single-joint isometric task. Therefore, the changes in muscle activity reported previously during similar tasks are unlikely to systematically reduce load in the painful region. Whether the individual-specific increase and decrease are physiologically relevant or purposeful requires further investigation.

Putative pain‐like states alter the discriminative stimulus effects of morphine in mice dependent on sex

Sex‐differences in pain sensitivity, opioid analgesia, and reinforcing effects of opioids are observed in rodents. The purpose of our study is to test the hypothesis that the presence of an acute noxious stimulus and/or chemotherapy‐induced chronic neuropathy will reduce the potency of morphine to produce discriminative stimulus effects in mice. Saline and morphine (3.2 mg/kg) were established as discriminative stimuli for food‐reinforced responses using a two‐choice operant training procedure in male and female C57Bl6 mice. After obtaining morphine dose‐response curves, mice were tested with acetic acid (0.4% conc.)+ morphine combinations to determine the effects of noxious stimulus on morphine potency. Next, mice were administered with saline or the chemotherapeutic agent paclitaxel (8 mg/kg) on days 1, 3, 5, and 7 while training was suspended for a week. Morphine dose‐curves were re‐established between days 8–14 post‐paclitaxel treatment (period of peak allodynia). The presence of an acute noxious stimulus and chemotherapy‐induced chronic neuropathy significantly decreased the potency of morphine to function as a discriminative cue in male but not in female mice suggesting a differential modulation of the stimulus effects of morphine in the presence of pain between sexes. Overall, these results may have implications for the understanding of potential sex differences in the clinical management of pain and abuse liability of prescription opioids in humans. (Supported by R01 CA129092).

Extracellular signal‐regulated kinase activation in the chronic constriction injury model of neuropathic pain in anaesthetized rats

The role of extracellular signal-regulated kinases (ERKs) in nociception has been explored in the last years. While in spinal cord their activation is frequently correlated with pain or acute noxious stimuli, supraspinally, this association is not so evident and remains unclear. This study aims to evaluate ERK1/2 activation in the spinal cord and brainstem nuclei upon neuropathy and/or an additional mechanical stimulus. Acute noxious mechanical stimulation was applied in the left hindpaw of anaesthetized SHAM-operated and chronic constriction injured (CCI, neuropathic pain model) rats. Other SHAM or CCI rats did not receive any stimulus. Immunohistochemistry against the phosphorylated isoforms of ERK1/2 (pERK1/2) was performed in lumbar spinal cord and brainstem sections to assess ERK1/2 activation. In the spinal cord, stimulation promoted an increase in pERK1/2 expression in the superficial dorsal horn of SHAM rats. No significant effects were caused by CCI alone. At supraspinal level, changes in ERK1/2 activation induced by CCI were observed in A5, locus coeruleus (LC), raphe obscurus (ROb), raphe magnus, dorsal raphe (DRN), lateral reticular and paragigantocellularis nucleus. CCI increased pERK1/2 expression in all these nuclei, with exception of LC, where a significant decrease was verified. Mechanical noxious stimulation of CCI rats decreased pERK1/2 expression in ROb and DRN, but no further changes were detected in either SHAM- or CCI-stimulated animals. ERK1/2 are differentially activated in the spinal cord and in selected brainstem nuclei implicated in nociception, in response to an acute noxious stimulus and/or to a neuropathic pain condition.

Acute noxious stimulus differentially alters morphine‐induced operant behavior in male and female mice

Fewer studies measure pain‐depressed relative to stimulus‐evoked behaviors in preclinical rodent pain models and even fewer studies use both male and female mice. The purpose of the present study is to test the hypothesis that the presence of an acute noxious stimulus will decrease food‐maintained operant behavior and reduce the potency of morphine to produce discriminative stimulus effects. Firstly, mice were trained to respond on a fixed ratio schedule to 50% ensure solution. In this assay, acetic acid (0.2–0.4%) produced concentration‐dependent suppression of responding in mice that was dose‐dependently prevented by morphine (0.32–3.2 mg/kg). Subsequently, male and female C67Bl/6 mice were trained in a two choice operant procedure to discriminate 3.2 mg/kg morphine or saline following which the dose response curves were generated in the absence and presence of 0.4% acetic acid. Morphine produced dose‐dependent drug‐appropriate responding in both male and female mice with no observed potency differences. However, male mice were significantly less sensitive to morphine and acetic acid‐induced effects on operant response rates. Importantly, the presence of acute noxious stimulus failed to alter the discriminative effects of morphine in female mice but significantly attenuated in male mice. In summary, pain‐depressed operant behavior and morphine‐induced discriminative effects may be differentially modulated in male and female mice suggesting the importance of sex differences in the clinical effectiveness of opioids and the abuse liability of morphine in the presence of pain. (Supported by CA129092)

Effects of the Delta Opioid Receptor Agonist SNC80 on Pain-Related Depression of Intracranial Self-Stimulation (ICSS) in Rats

The delta opioid receptor agonist SNC80 produces both antinociceptive and antidepressant effects in rodents. This profile suggests that SNC80 may also reverse prodepressant effects of pain. Accordingly, this study compared SNC80 effects in complementary assays of pain-stimulated and pain-depressed behavior in rats. Intraperitoneal injection of dilute acid served as an acute noxious visceral stimulus in rats to stimulate abdominal stretching (a pain-stimulated behavior) or depress intracranial self-stimulation of the medial forebrain bundle (ICSS; a pain-depressed behavior). When administered once per week to minimize acute tolerance, SNC80 (1–10 mg/kg IP) decreased acid-stimulated stretching but had little effect on acid-induced depression of ICSS. More frequent SNC80 administration produced tolerance to SNC80 effects on acid-stimulated stretching, but unmasked antinociception in the assay of acid-depressed ICSS. SNC80 did not facilitate ICSS in the absence of pain, and effects of SNC80 were not duplicated by ARM390, a reputed delta agonist congener of SNC80 that does not internalize delta receptors. These findings support continued consideration of delta agonists as candidate analgesics to treat prodepressant effects of pain and illustrate the potential for diametrically opposite effects of drug treatments on preclinical measures of pain-stimulated and pain-depressed behavior. PerspectiveThe delta opioid agonist SNC80 blocked pain-related depression of intracranial self-stimulation in rats, suggesting that delta agonists may be useful to treat prodepressant effects of pain. Repeated SNC80 produced tolerance to SNC80 antinociception in a conventional assay of pain-stimulated behavior but unmasked SNC80 antinociception in an assay of pain-depressed behavior.

Antinociceptive Effect of Riluzole in Rats with Neuropathic Spinal Cord Injury Pain

Symptoms of neuropathic spinal cord injury (SCI) pain include cutaneous hypersensitivity and spontaneous pain below the level of the injury. Riluzole, an FDA-approved drug for the treatment of amyotrophic lateral sclerosis, has been demonstrated to attenuate neural excitotoxicity by blocking the effects of the excitatory amino acid glutamate on glutamate receptors and by inhibiting voltage-gated Na(+) and Ca(2+) channels. Neuropathic pain in rat models of SCI is thought to be mediated by dysfunctional ion channels and glutamate receptors expressed on CNS neurons. Thus riluzole's mechanism of action could be relevant in treating neuropathic SCI pain. The current study evaluated the antinociceptive potential of riluzole in rats following a SCI. Four weeks after a brief compressive injury to the mid-thoracic spinal cord, rats displayed significantly decreased hind paw withdrawal thresholds, suggestive of below-level cutaneous hypersensitivity. A single systemic dose of riluzole (8 mg/kg) injected intraperitoneally (i.p.) reversed cutaneous hypersensitivity in SCI rats. To identify riluzole's CNS site of action, riluzole was injected intrathecally (i.t.) and intracerebroventricularly (i.c.v.) in SCI rats. Significant antinociceptive effects were obtained following i.c.v., but not i.t., injection. Systemic riluzole was also antinociceptive in uninjured rats, increasing the latency to respond to an acute noxious thermal stimulus in the tail flick test. Unlike in SCI rats, however, riluzole was not effective when administered directly into the CNS, indicating a peripherally mediated antinociceptive mechanism. Although riluzole appears to have a general antinociceptive effect, the site of action may be model dependent. In total, these data indicate that riluzole may be an effective clinical analgesic for the treatment of below-level neuropathic SCI pain. Although the exact mechanism of action is not clear, there is a predominant supraspinal component of riluzole-induced antinociception in SCI rats.

The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys

The synthetic nonpeptide NOP (nociceptin/orphanin FQ peptide) receptor agonist Ro 64-6198 produces antinociception in rhesus monkeys. In rodents, it has much more variable effects on pain responses, but has response rate-increasing effects on punished operant behavior and decreases drug reward. The aim of this study was to compare Ro 64-6198 with the benzodiazepine diazepam in tests of analgesia, drug self-administration, and response-increasing effects in rhesus monkeys. Ro 64-6198 (0.001-0.01 mg/kg, i.v.) produced antinociception against an acute noxious stimulus (50°C water) in the absence of sedation, whereas diazepam (0.32-3.2 mg/kg, i.v.) did not have analgesic effects without sedation. Diazepam (1.0-5.6 mg/kg, i.v.) and the largest dose of Ro 64-6198 (0.32 mg/kg, i.v.) decreased lever pressing maintained by intravenous self-administration of the mu-opioid agonist, remifentanil, but neither effect could be distinguished from sedative effects. Although neither drug consistently increased responding during nonreinforcement, such effects were observed more frequently following diazepam administration. The effects of Ro 64-6198 on lever pressing were blocked by the NOP-receptor antagonist, J-113397, but not by the benzodiazepine antagonist, flumazenil. These findings suggest that the effects of Ro 64-6198 on operant lever pressing are mediated by NOP receptors and that larger doses are required to impact operant behavior when compared directly with those that produce antinociception. Therefore, the present findings support previous literature suggesting NOP receptors are a viable target for pain management.

The effects of Ro 64‐6198 and diazepam on antinociception and remifentanil self‐administration in rhesus monkeys

The aim of this study was to compare the behavioral effects of a synthetic nonpeptidic NOP (nociceptin/orphanin FQ Peptide) receptor agonist, Ro 64‐6198, with a benzodiazepine, diazepam, in rhesus monkeys. Ro 64‐6198 (0.001–0.01 mg/kg, i.v.) produced antinociception against an acute noxious stimulus (50 degrees C water), but diazepam (0.32–3.2 mg/kg, i.v.) did not produce such effects at any dose tested. Higher doses of Ro 64‐6198 (0.32 mg/kg, i.v.) and diazepam (1.0–5.6 mg/kg, i.v.) decreased lever pressing maintained by intravenous self‐administration of the mu‐opioid agonist, remifentanil. Although neither drug increased nonreinforced responding with complete consistency, such effects were more frequent with diazepam. These effects of Ro 64‐6198 on lever pressing were blocked by an NOP‐receptor antagonist, J‐113397, but not by the benzodiazepine antagonist, flumazenil. Conversely, the effects of diazepam on lever pressing were blocked by flumazenil but not J‐113397. These findings suggest the effects of Ro 64‐6198 on operant lever pressing are mediated by NOP receptors and that higher doses are required compared to those producing antinociception. Moreover, Ro 64‐6198 was less likely to disinhibit nonreinforced operant responding than diazepam, suggesting diazepam might produce greater anxiolytic‐like effects than Ro 64‐6198 in rhesus monkeys.

Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112

Chemical modifications of nociceptin/orphanin FQ (N/OFQ) peptide that result in increased potency and resistance to degradation have recently lead to the discovery of [(pF)Phe 4Aib 7Arg 14Lys 15]N/OFQ-NH 2 (UFP-112), a novel N/OFQ peptide (NOP) receptor agonist. The aim of this study was to investigate the pharmacological profile of intrathecally administered UFP-112 in monkeys under different behavioral assays. Intrathecal UFP-112 (1–10 nmol) dose-dependently produced antinociception against an acute noxious stimulus (50 °C water) and capsaicin-induced thermal hyperalgesia. Intrathecal UFP-112-induced antinociception could be reversed by a NOP receptor antagonist, J-113397 (0.1 mg/kg), but not by a classic opioid receptor antagonist, naltrexone (0.03 mg/kg). Like intrathecal morphine, UFP-112 produced antinociception in two primate pain models with a similar magnitude of effectiveness and a similar duration of action that last for 4–5 h. Unlike intrathecal morphine, UFP-112 did not produce itch/scratching responses. In addition, intrathecal inactive doses of UFP-112 and morphine produced significant antinociceptive effects when given in combination without increasing scratching responses. These results demonstrated that intrathecal UFP-112 produced long-lasting morphine-comparable antinociceptive effects without potential itch side effect. This study is the first to provide functional evidence that selective NOP receptor agonists such as UFP-112 alone or in conjunction with morphine may improve the quality of spinal analgesia.