The periaqueductal gray (PAG) is a complex mesencephalic structure involved in the integration and execution of active and passive self-protective behaviors against imminent threats, such as immobility or flight from a predator. PAG activity is also associated with the integration of responses against physical discomfort (e.g., anxiety, fear, pain, and disgust) which occurs prior an imminent attack, but also during withdrawal from drugs such as morphine and cocaine. The PAG sends and receives projections to and from other well-documented nuclei linked to the phenomenon of drug addiction including: (i) the ventral tegmental area; (ii) extended amygdala; (iii) medial prefrontal cortex; (iv) pontine nucleus; (v) bed nucleus of the stria terminalis; and (vi) hypothalamus. Preclinical models have suggested that the PAG contributes to the modulation of anxiety, fear, and nociception (all of which may produce physical discomfort) linked with chronic exposure to drugs of abuse. Withdrawal produced by the major pharmacological classes of drugs of abuse is mediated through actions that include participation of the PAG. In support of this, there is evidence of functional, pharmacological, molecular. And/or genetic alterations in the PAG during the impulsive/compulsive intake or withdrawal from a drug. Due to its small size, it is difficult to assess the anatomical participation of the PAG when using classical neuroimaging techniques, so its physiopathology in drug addiction has been underestimated and poorly documented. In this theoretical review, we discuss the involvement of the PAG in drug addiction mainly via its role as an integrator of responses to the physical discomfort associated with drug withdrawal.
Amygdala ; Humans ; Morphine ; Nociception ; Periaqueductal Gray ; Substance-Related Disorders

Dysregulation of excitatory neurotransmission has been implicated in the pathogenesis of neuropsychiatric disorders. Pharmacological inhibition of N-methyl-D-aspartate (NMDA) receptors is widely used to model neurobehavioral pathologies and underlying mechanisms. There is ample evidence that overstimulation of NMDA-dependent neurotransmission may induce neurobehavioral abnormalities, such as repetitive behaviors and hypersensitization to nociception and cognitive disruption, pharmacological modeling using NMDA has been limited due to the induction of neurotoxicity and blood brain barrier breakdown, especially in young animals. In this study, we examined the effects of intraperitoneal NMDA-administration on nociceptive and repetitive behaviors in ICR mice. Intraperitoneal injection of NMDA induced repetitive grooming and tail biting/licking behaviors in a dose- and age-dependent manner. Nociceptive and repetitive behaviors were more prominent in juvenile mice than adult mice. We did not observe extensive blood brain barrier breakdown or neuronal cell death after peritoneal injection of NMDA, indicating limited neurotoxic effects despite a significant increase in NMDA concentration in the cerebrospinal fluid. These findings suggest that the observed behavioral changes were not mediated by general NMDA toxicity. In the hot plate test, we found that the latency of paw licking and jumping decreased in the NMDA-exposed mice especially in the 75 mg/kg group, suggesting increased nociceptive sensitivity in NMDA-treated animals. Repetitive behaviors and increased pain sensitivity are often comorbid in psychiatric disorders (e.g., autism spectrum disorder). Therefore, the behavioral characteristics of intraperitoneal NMDA-administered mice described herein may be valuable for studying the mechanisms underlying relevant disorders and screening candidate therapeutic molecules.
Adult ; Animals ; Autistic Disorder ; Blood-Brain Barrier ; Cell Death ; Cerebrospinal Fluid ; Grooming ; Humans ; Injections, Intraperitoneal ; Mass Screening ; Mice ; Mice, Inbred ICR ; N-Methylaspartate ; Neurons ; Nociception ; Pathology ; Synaptic Transmission ; Tail

The present study was conducted to investigate anti-nociceptive and anti-inflammatory effects of the leaves of Ilex latifolia Thunb (I. latifolia) in in vivo and in vitro. Writhing responses induced by acetic acid and formalin- and thermal stimuli (tail flick and hot plate tests)-induced pain responses for nociception were evaluated in mice. I. latifolia (50 – 200 mg/kg, p.o.) and ibuprofen (100 mg/kg, p.o.), a positive non-steroidal anti-inflammatory drug (NSAID), inhibited the acetic acid-induced writhing response and the second phase response (peripheral inflammatory response) in the formalin test, but did not protect against thermal nociception and the first phase response (central response) in the formalin test. These results show that I. latifolia has a significant anti-nociceptive effect that appears to be peripheral, but not central. Additionally, I. latifolia (50 and 100 µg/mL) and 3,5-di-caffeoyl quinic acid methyl ester (5 µM) isolated from I. latifolia as an active compound significantly inhibited LPS-induced NO production and mRNA expression of the pro-inflammatory mediators, iNOS and COX-2, and the pro-inflammatory cytokines, IL-6 and IL-1β, in RAW 264.7 macrophages. These results suggest that I. latifolia can produce antinociceptive effects peripherally, but not centrally, via anti-inflammatory activity and supports a possible use of I. latifolia to treat pain and inflammation.
Acetic Acid ; Animals ; Cyclooxygenase 2 ; Cytokines ; Ibuprofen ; Ilex ; In Vitro Techniques ; Inflammation ; Interleukin-6 ; Macrophages ; Mice ; Nitric Oxide ; Nociception ; Pain Measurement ; Quinic Acid ; RNA, Messenger

BACKGROUND/AIMS: Abdominal pain can be evoked or exacerbated after gastrointestinal cold stimulation in some patients with diarrhea-predominant irritable bowel syndrome (IBS-D), indicating a low temperature-induced sensitization of visceral perception. We investigated the role of vagal transient receptor potential ankyrin 1 (TRPA1, a cold-sensing ion channel) in cold-aggravated visceral mechanonociception in a stress-induced IBS animal model. METHODS: TRPA1 expression was examined in antral biopsies of healthy controls and IBS-D patients. Abdominal symptoms were assessed before and after warm or cold water intake. The visceromotor response (VMR) to colorectal distention (CRD) following intra-antral infusion of cold saline was measured in animals undergoing sham or chronic water avoidance stress. TRPA1 expression, extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation, and neuronal calcium influx in vagal afferents were assessed. RESULTS: Compared to healthy controls, IBS-D patients displayed elevated antral TRPA1 expression, which was associated with symptom scores after cold (4°C) water intake. Intra-antral infusion of cold saline increased VMR to CRD in naive rats, an effect dependent on vagal afferents. In stressed rats, this effect was greatly enhanced. Functional blockade and gene deletion of TRPA1 abolished the cold effect on visceral nociception. TRPA1 expression in vagal (but not spinal) afferents increased after stress. Moreover, the cold-induced, TRPA1-dependent ERK1/2 activation and calcium influx in nodose neurons were more robust in stressed rats. CONCLUSIONS: Stress-exaggerated visceral mechanonociception after antral cold exposure may involve up-regulation of TRPA1 expression and function on vagal afferents. Our findings reveal a novel mechanism for abnormal gastrointestinal cold sensing in IBS.
Abdominal Pain ; Animals ; Ankyrins ; Biopsy ; Calcium ; Cold Temperature ; Drinking ; Gene Deletion ; Humans ; Irritable Bowel Syndrome ; Models, Animal ; Neurons ; Nociception ; Phosphorylation ; Protein Kinases ; Rats ; Stress, Psychological ; Up-Regulation ; Vagus Nerve ; Visceral Pain ; Water

Nociception monitoring devices using changes in autonomic nervous system activity have been developed in numerous ways. Although there have been few studies conducted on children, compared to the relatively higher number of studies on adults, most of the nociception monitors in children, as in adults, appear to be more useful than the standard clinical practice that uses hemodynamic parameters in the evaluation and treatment of intraoperative nociception (pain) during general anesthesia. Particularly, when monitoring the surgical pleth index (SPI) in anesthetized children, the application of a new target range of SPI values (≤ 40) to the SPI monitoring criteria seems to be necessary for providing a more proper intraoperative analgesia. The analgesia nociception index (ANI) shows promising results in anesthetized adults, and recently, positive results along with cardiorespiratory coherence have been reported in pediatric patients. Newborn infant parasympathetic evaluation (NIPE) could be useful for providing adequate analgesia in newborns, infants, and children under 2 years of age in anesthetized or awake states. In cases of skin conductance and pupillometry, further studies are needed. Understanding the pros, cons, and limitations of these nociception monitoring tools will provide more effective and safe intraoperative analgesia to pediatric patients undergoing general anesthesia, and it may also help to plan and conduct promising research on the use of perioperative nociception monitoring in pediatric patients in the future.
Adult ; Analgesia ; Anesthesia, General ; Autonomic Nervous System ; Child ; Hemodynamics ; Humans ; Infant ; Infant, Newborn ; Monitoring, Intraoperative ; Nociception ; Pain Measurement ; Skin

BACKGROUND: Brennan’s rodent paw incision model has been extensively used for understanding mechanisms underlying postoperative pain in humans. However, alterations of physiological parameters like blood pressure and heart rate, or even feeding and drinking patterns after the incision have not been documented as yet. Moreover, though eicosanoids like prostaglandins and leukotrienes contribute to inflammation, tissue levels of these inflammatory mediators have never been studied. This work further investigates the antinociceptive effect of protein C after intra-wound administration. METHODS: Separate groups of Sprague–Dawley rats were used for quantitation of cyclooxygenase (COX) activity and leukotriene B4 level by enzyme-linked immunosorbent assay, as well as estimation of cardiovascular parameters and feeding and drinking behavior after paw incision. In the next part, rats were subjected to incision and 10 μg of protein C was locally administered by a micropipette. Both evoked and non-evoked pain parameters were then estimated. RESULTS: COX, particularly COX-2 activity and leukotriene B4 levels increased after incision. Hemodynamic parameters were normal. Feeding and drinking were affected on days 1 and 3, and on day 1, respectively. Protein C attenuated non-evoked pain behavior alone up to day 2. CONCLUSIONS: Based upon current observations, Brennan’s rodent paw incision model appears to exhibit a prolonged period of nociception similar to that after surgery, with minimal interference of physiological parameters. Protein C, which is likely converted to activated protein C in the wound, attenuated the guarding score, which probably represents pain at rest after surgery in humans.
Animals ; Blood Pressure ; Drinking ; Drinking Behavior ; Eicosanoids ; Enzyme-Linked Immunosorbent Assay ; Heart Rate ; Hemodynamics ; Humans ; Inflammation ; Leukotriene B4 ; Leukotrienes ; Nociception ; Pain, Postoperative ; Prostaglandin-Endoperoxide Synthases ; Prostaglandins ; Protein C ; Rats ; Rodentia ; Wounds and Injuries

The lamina II, also called the substantia gelatinosa (SG), of the trigeminal subnucleus caudalis (Vc), is thought to play an essential role in the control of orofacial nociception. Glycine and serotonin (5-hydroxytryptamine, 5-HT) are the important neurotransmitters that have the individual parts on the modulation of nociceptive transmission. However, the electrophysiological effects of 5-HT on the glycine receptors on SG neurons of the Vc have not been well studied yet. For this reason, we applied the whole-cell patch clamp technique to explore the interaction of intracellular signal transduction between 5-HT and the glycine receptors on SG neurons of the Vc in mice. In nine of 13 neurons tested (69.2%), pretreatment with 5-HT potentiated glycine-induced current (I(Gly)). Firstly, we examined with a 5-HT₁ receptor agonist (8-OH-DPAT, 5-HT(1/7) agonist, co-applied with SB-269970, 5-HT₇ antagonist) and antagonist (WAY-100635), but 5-HT₁ receptor agonist did not increase IGly and in the presence of 5-HT₁ antagonist, the potentiation of 5-HT on I(Gly) still happened. However, an agonist (α-methyl-5-HT) and antagonist (ketanserin) of the 5-HT₂ receptor mimicked and inhibited the enhancing effect of 5-HT on I(Gly) in the SG neurons, respectively. We also verified the role of the 5-HT₇ receptor by using a 5-HT₇ antagonist (SB-269970) but it also did not block the enhancement of 5-HT on I(Gly). Our study demonstrated that 5-HT facilitated I(Gly) in the SG neurons of the Vc through the 5-HT₂ receptor. The interaction between 5-HT and glycine appears to have a significant role in modulating the transmission of the nociceptive pathway.
Animals ; Glycine ; Mice ; Neurons ; Neurotransmitter Agents ; Nociception ; Patch-Clamp Techniques ; Receptors, Glycine ; Serotonin ; Signal Transduction ; Substantia Gelatinosa

The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) has been an object of intense interest for pharmacological development on account of its critical role in nociception. In the course of structure activity analysis, it has become apparent that TRPV1 ligands may vary dramatically in the rates at which they interact with TRPV1, presumably reflecting differences in their abilities to penetrate into the cell. Using a fast penetrating agonist together with an excess of a slower penetrating antagonist, we find that we can induce an agonist response of limited duration and, moreover, the duration of the agonist response remains largely independent of the absolute dose of agonist, as long as the ratio of antagonist to agonist is held constant. This general approach for limiting agonist duration under conditions in which absolute agonist dose is variable should have more general applicability.
Capsaicin ; Ligands ; Nociception

BACKGROUND: Curcumin is traditionally used as an herbal medicine. We explored the efficacy of intrathecal curcumin in relieving both postoperative and inflammatory pain and elucidated the mechanisms of action of curcumin interacting with γ-aminobutyric acid (GABA) and opioid receptors at the spinal level. METHODS: Experimental pain was induced in male Sprague-Dawley rats via paw incision or injection of intraplantar carrageenan. After examination of the effects of intrathecal curcumin on the pain, GABA and opioid receptor antagonists were intrathecally administered to explore the involvement of GABA or opioid receptors on the effect of curcumin. Additionally, the expression levels of the GABA and opioid receptors were assessed. RESULTS: Intrathecal curcumin reduced the withdrawal threshold of both incisional surgery- and carrageenan injection-induced nociception. Intrathecal GABA and opioid receptor antagonists reversed the curcumin-mediated antinociception. Incisional surgery decreased the levels of the GABA receptors mRNA, but little changed the levels of the opioid receptors mRNA. Carrageenan injection increased the levels of the opioid receptors mRNA, but not the GABA receptors mRNA levels. Intrathecal curcumin increased or decreased the levels of GABA receptors mRNA and opioid receptors mRNA in the spinal cords of incised or carrageenan-injected rats, respectively. CONCLUSIONS: Intrathecal curcumin was effective to postoperative and inflammatory pain and such antinociception of curcumin was antagonized by both GABA and opioid receptor antagonists. Also, intrathecal curcumin altered the levels of GABA and opioid receptors. Thus, spinal GABA and opioid receptors may, respectively, be directly or indirectly involved when curcumin alleviates postoperative and inflammatory pain.
Animals ; Carrageenan ; Curcumin ; gamma-Aminobutyric Acid ; Herbal Medicine ; Humans ; Male ; Narcotic Antagonists ; Nociception ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA ; Receptors, Opioid ; RNA, Messenger ; Spinal Cord

Accumulating evidence suggests that obesity is associated with chronic pain. However, whether obesity is associated with acute inflammatory pain is unknown. Using a well-established obese mouse model induced by a high-fat diet, we found that: (1) the acute thermal pain sensory threshold did not change in obese mice; (2) the model obese mice had fewer nociceptive responses in formalin-induced inflammatory pain tests; restoring the obese mice to a chow diet for three weeks partly recovered their pain sensation; (3) leptin injection induced significant phosphorylation of STAT3 in control mice but not in obese mice, indicating the dysmodulation of topical leptin-leptin receptor signaling in these mice; and (4) leptin-leptin receptor signaling-deficient mice (ob/ob and db/db) or leptin-leptin receptor pathway blockade with a leptin receptor antagonist and the JAK2 inhibitor AG 490 in wild-type mice reduced their nociceptive responses in formalin tests. These results indicate that leptin plays a role in nociception induced by acute inflammation and that interference in the leptin-leptin receptor pathway could be a peripheral target against acute inflammatory pain.
Animals ; Diet, High-Fat ; adverse effects ; Inflammation ; chemically induced ; metabolism ; Leptin ; metabolism ; pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Nociception ; drug effects ; physiology ; Nociceptive Pain ; etiology ; metabolism ; Obesity ; complications ; metabolism ; Pain Measurement ; Pain Threshold ; drug effects ; physiology ; Receptors, Leptin ; metabolism ; Signal Transduction ; drug effects ; physiology