Concentration-effect Relations for Intravenous Lidocaine Infusions in Human Volunteers 

1997 ◽  
Vol 86 (6) ◽  
pp. 1262-1272 ◽  
Author(s):  
Mark S. Wallace ◽  
Steve Laitin ◽  
Darren Licht ◽  
Tony L. Yaksh
Keyword(s):  
Tissue Injury ◽  
Infusion Pump ◽  
Afferent Input ◽  
Preclinical Studies ◽  
Mechanical Stimuli ◽  
Intravenous Lidocaine ◽  
Test Stimulation ◽  
Plasma Lidocaine ◽  
Human Volunteers ◽  
Flare Response

Background Preclinical studies have emphasized that persistent small afferent input will induce a state of central facilitation that can be regulated by systemically administered lidocaine. The authors extended these preclinical studies to human volunteers by examining the concentration-dependent effects of intravenous lidocaine on acute sensory thresholds and facilitated processing induced by intradermal capsaicin. Methods Fifteen healthy persons received a lidocaine or a placebo infusion. A computer-controlled infusion pump targeted sequential stepwise increases in plasma lidocaine concentration steps of 1, 2, and 3 microg/ml. At each plasma concentration, neurosensory testing (thermal and von Frey hair test stimulation) were performed. After completing the tests at the 3 microg/ml plasma lidocaine level, intradermal capsaicin was injected into the volar aspect of the left forearm, and the flare response and hyperalgesia to von Frey hair stimulation, stroking, and heat was assessed. Results The continuous infusion of lidocaine and placebo had no significant effect on any stimulus threshold. Although intravenous lidocaine resulted in a decrease in all secondary hyperalgesia responses, this was only significant for heat hyperalgesia. Intravenous lidocaine resulted in a significant decrease in the flare response induced by intradermal capsaicin. Conclusions These studies suggest that the facilitated state induced by persistent small afferent input human pain models may predict the activity of agents that affect components of nociceptive processing that are different from those associated with the pain state evoked by "acute" thermal or mechanical stimuli. Such insight may be valuable in the efficient development of novel analgesics for both neuropathic and post-tissue-injury pain states.

Long-term effects of early pain and injury

2021 ◽  
pp. 21-37
Author(s):  
Orla Moriarty ◽  
Suellen M. Walker
Keyword(s):  
Nervous System ◽  
Early Life ◽  
Tissue Injury ◽  
Afferent Input ◽  
Laboratory Studies ◽  
Long Term Effects ◽  
Nociceptive Pathways ◽  
Noxious Stimuli ◽  
Underlying Mechanisms

Nociceptive pathways are functional following birth, and acute responses to noxious stimuli have been documented from early in development in clinical and laboratory studies. The ability of noxious afferent input to alter the level of sensitivity of nociceptive pathways in the adult nervous system, with, for example, the development of central sensitization, is well established. However, the developing nervous system has additional susceptibilities to alterations in neural activity, and pain in early life may produce effects not seen following the same input at older ages. As a result, early tissue injury may lead to persistent changes in somatosensory processing and altered sensitivity to future noxious stimuli. Furthermore, there is increasing evidence that neonatal pain can result in long-term changes in cognitive and affective behavior. Effects of pain in early life are superimposed on a highly plastic developing system, and long-term outcomes vary depending on the type and severity of the injury, and on the evaluation methods used. Laboratory studies allow evaluation of different injuries, potential confounding factors, underlying mechanisms, and potential analgesic modulation.

Long-term effects of early pain and injury: animal models

2013 ◽  
pp. 20-29 ◽  
Author(s):  
Suellen M. Walker
Keyword(s):  
Nervous System ◽  
Tissue Injury ◽  
Afferent Input ◽  
Somatosensory Processing ◽  
Laboratory Studies ◽  
Long Term Effects ◽  
Nociceptive Pathways ◽  
Acute Responses ◽  
Noxious Stimuli ◽  
Underlying Mechanisms

Nociceptive pathways are functional following birth and acute responses to noxious stimuli have been documented from early development in both clinical and laboratory studies. The ability of noxious afferent input to alter the level of sensitivity of nociceptive pathways in the adult nervous system, with, for example the development of central sensitization, is well established (Woolf, 2011). However, the developing nervous system has additional susceptibilities to alterations in neural activity, and increases due to pain and injury in early life may produce effects not seen following the same input at older ages. As a result, early tissue injury may lead to persistent changes in somatosensory processing and altered sensitivity to future noxious stimuli. The impact of early pain and injury cannot be simply viewed as increasing or decreasing sensitivity as results vary depending on the type and severity of injury and the outcomes used for assessment. Laboratory studies allow evaluation of different forms of injury, potential confounding factors, underlying mechanisms, and potential for modulation by analgesia.

Orexin-A modulates glutamatergic NMDA-dependent spinal reflex potentiation via inhibition of NR2B subunit

2008 ◽  
Vol 295 (1) ◽  
pp. E117-E129 ◽  
Author(s):  
Hsien-Yu Peng ◽  
Hung-Ming Chang ◽  
Sarah Y. Chang ◽  
Kwong-Chung Tung ◽  
Shin-Da Lee ◽  
...  
Keyword(s):  
Afferent Input ◽  
Spinal Reflex ◽  
Reflex Activity ◽  
Nr2b Subunit ◽  
Orexin A ◽  
Hypothalamic Area ◽  
Available N ◽  
Test Stimulation ◽  
Neural Transmission ◽  
Novel Target

Glucose-sensitive neurons in the lateral hypothalamic area produce orexin-A (OxA) as well as orexin-B (OxB) and send their axons to the spinal dorsal horn, which predominantly expresses orexin receptor-1 (OX-1), showing a higher sensitivity to OxA. The purpose of the present study was to assess the effects of OxA on the induction of a novel form of activity-dependent reflex potentiation, spinal reflex potentiation (SRP), in the pelvic-urethral reflex activity. External urethra sphincter electromyogram in response to pelvic afferent nerve test stimulation (TS; 1/30 Hz) or repetitive stimulation (RS; 1 Hz) was recorded in anesthetized rats. TS evoked a baseline reflex activity, whereas RS produced SRP, which was abolished by intrathecal OxA (30 nM, 10 μl). Intrathecal SB-408124 (10 μM, 10 μl), an OX-1 antagonist, reversed the abolition on SRP caused by OxA. Although there is, so far, no NR2A- and NR2B-specific agonist available, N-methyl-d-aspartate (NMDA) reversed the abolition on the RS-induced SRP caused by the co-administration of OxA and Co-101244 (30 nM, 10 μl; an NMDA NR2B subunit antagonist), but it did not reverse the abolition by the co-administration of OxA and PPPA (300 nM, 10 μl; an NMDA NR2A subunit antagonist). In conclusion, the activation of descending orexinergic fibers may inhibit the repetitive afferent input-induced central sensitization of pelvic-urethral reflex activity and urethra hyperactivity, indicating that spinal orexinergic neural transmission may be a novel target for the treatment of patients with neuropathetic or postinflammatory pain of pelvic origin.

scholarly journals Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRα3

2016 ◽  
Vol 113 (16) ◽  
pp. 4506-4511 ◽  
Author(s):  
Erika K. Lippoldt ◽  
Serra Ongun ◽  
Geoffrey K. Kusaka ◽  
David D. McKemy
Keyword(s):  
Chronic Pain ◽  
Neurotrophic Factor ◽  
Neutralizing Antibodies ◽  
Tissue Injury ◽  
Cold Sensitivity ◽  
Mechanical Stimuli ◽  
Cold Pain ◽  
Cold Allodynia ◽  
Cold Sensitive ◽  
Striking Contrast

Tissue injury prompts the release of a number of proalgesic molecules that induce acute and chronic pain by sensitizing pain-sensing neurons (nociceptors) to heat and mechanical stimuli. In contrast, many proalgesics have no effect on cold sensitivity or can inhibit cold-sensitive neurons and diminish cooling-mediated pain relief (analgesia). Nonetheless, cold pain (allodynia) is prevalent in many inflammatory and neuropathic pain settings, with little known of the mechanisms promoting pain vs. those dampening analgesia. Here, we show that cold allodynia induced by inflammation, nerve injury, and chemotherapeutics is abolished in mice lacking the neurotrophic factor receptor glial cell line-derived neurotrophic factor family of receptors-α3 (GFRα3). Furthermore, established cold allodynia is blocked in animals treated with neutralizing antibodies against the GFRα3 ligand, artemin. In contrast, heat and mechanical pain are unchanged, and results show that, in striking contrast to the redundant mechanisms sensitizing other modalities after an insult, cold allodynia is mediated exclusively by a single molecular pathway, suggesting that artemin–GFRα3 signaling can be targeted to selectively treat cold pain.

scholarly journals Mechanoregulation of YAP and TAZ in Cellular Homeostasis and Disease Progression

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaomin Cai ◽  
Kuei-Chun Wang ◽  
Zhipeng Meng
Keyword(s):  
Cell Fate ◽  
Vascular System ◽  
Tissue Injury ◽  
Hippo Pathway ◽  
Critical Role ◽  
Cell Interaction ◽  
Tissue Growth ◽  
Cyclic Stretch ◽  
Mechanical Stimuli ◽  
Hemodynamic Forces

Biophysical cues, such as mechanical properties, play a critical role in tissue growth and homeostasis. During organ development and tissue injury repair, compressive and tensional forces generated by cell-extracellular matrix or cell-cell interaction are key factors for cell fate determination. In the vascular system, hemodynamic forces, shear stress, and cyclic stretch modulate vascular cell phenotypes and susceptibility to atherosclerosis. Despite that emerging efforts have been made to investigate how mechanotransduction is involved in tuning cell and tissue functions in various contexts, the regulatory mechanisms remain largely unknown. One of the challenges is to understand the signaling cascades that transmit mechanical cues from the plasma membrane to the cytoplasm and then to the nuclei to generate mechanoresponsive transcriptomes. YAP and its homolog TAZ, the Hippo pathway effectors, have been identified as key mechanotransducers that sense mechanical stimuli and relay the signals to control transcriptional programs for cell proliferation, differentiation, and transformation. However, the upstream mechanosensors for YAP/TAZ signaling and downstream transcriptome responses following YAP/TAZ activation or repression have not been well characterized. Moreover, the mechanoregulation of YAP/TAZ in literature is highly context-dependent. In this review, we summarize the biomechanical cues in the tissue microenvironment and provide an update on the roles of YAP/TAZ in mechanotransduction in various physiological and pathological conditions.

The use of Preoperative Lidocaine to Prevent Stridor and Laryngospasm after Tonsillectomy and Adenoidectomy

1998 ◽  
Vol 118 (6) ◽  
pp. 880-882 ◽  
Author(s):  
CAN KOÇ ◽  
FALIH KOCAMAN ◽  
ERDINÇ AYGENÇ ◽  
CAFER ÖZDEM ◽  
ALI ÇEKIÇ
Keyword(s):  
Early Postoperative Period ◽  
Control Group ◽  
Double Blind Study ◽  
Intravenous Lidocaine ◽  
Double Blind ◽  
Lidocaine Group ◽  
Group 4 ◽  
Topical Lidocaine ◽  
Plasma Lidocaine ◽  
Sedation Scores

The most important complications from tonsillectomy and adenoidectomy are bleeding, stridor, and laryngospasm. This controlled, double-blind study was designed to investigate the effects of topical and intravenous lidocaine on stridor and laryngospasm. A total of 134 patients scheduled for elective tonsillectomy and/or adenoidectomy were randomly separated into four groups. In the topical lidocaine group 4 mg/kg of 2% lidocaine was applied to subglottic, glottic, and supraglottic areas before endotracheal intubation. Normal saline solution was used topically for the first control group. In the intravenous lidocaine group, patients were given 1 mg/kg of 2% lidocaine before extubation, and the same amount of 0.9% NaCl was given to the second control group. Postoperative stridor, laryngospasm, cyanosis, bleeding, sedation degree, and respiratory depression were observed, and plasma lidocaine levels were measured. Both topical and intravenous lidocaine groups revealed less stridor and laryngospasm than the control groups, and no difference was found between the topical and intravenous lidocaine groups except the higher sedation scores in the early postoperative period for the intravenous lidocaine group. (Otolaryngol Head Neck Surg 1998;118:880–2.)

Characterization of Aδ- and C-Fibers Innervating the Plantar Rat Hindpaw One Day After an Incision

2002 ◽  
Vol 87 (2) ◽  
pp. 721-731 ◽  
Author(s):  
Esther M. Pogatzki ◽  
G. F. Gebhart ◽  
Timothy J. Brennan
Keyword(s):  
Spontaneous Activity ◽  
Mechanical Response ◽  
Tissue Injury ◽  
Mechanical Stimulus ◽  
Response Threshold ◽  
Mechanical Stimuli ◽  
Median Response ◽  
Sham Procedure ◽  
C Fibers ◽  
Afferent Fibers

Primary hyperalgesia after tissue injury is suggested to result from sensitization of primary afferent fibers, but sensitization to mechanical stimuli has been difficult to demonstrate. In the companion study, sensitization of mechano-responsive Aδ- and C-fibers did not explain pain behaviors 45 min after an incision in the rat hindpaw. In the present study, we examined mechanical response properties of Aδ- and C-fibers innervating the glabrous skin of the plantar hindpaw in rats 1 day after an incision or sham procedure. In behavioral experiments, median withdrawal thresholds to von Frey filaments were reduced from 522 mN before to 61 mN 2 and 20 h after incision; median withdrawal thresholds after sham procedure were stable (522 mN). Responses to a nonpunctate mechanical stimulus were increased after incision. In neurophysiological experiments in these same rats, 67 single afferent fibers were characterized from the left tibial nerve 1 day after sham procedure ( n = 39) or incision ( n = 28); electrical stimulation was used as the search stimulus to identify a representative population of Aδ- and C-fibers. In the incision group, 11 fibers (39%) had spontaneous activity with frequencies ranging from 0.03 to 39.3 imp/s; none were present in the sham group. The median response threshold of Aδ-fibers was less in the incision (56 mN, n = 13) compared with sham (251 mN, n = 26) group, mainly because the proportion of mechanically insensitive afferents (MIAs) was less (8 vs. 54% after sham procedure). Median C-fiber response thresholds were similar in incised (28 mN, n = 15) and sham rats (56 mN, n = 13). Responsiveness to monofilaments was significantly enhanced in Aδ-fibers 1 day after incision; stimulus response functions of C-fibers after incision and after sham procedure did not differ significantly. Only Aδ-fibers but not C-fibers sensitized to the nonpunctate mechanical stimulus. The size of receptive fields was increased in Aδ- and C-fibers 1 day after incision. The results indicate that sensitization of Aδ- and C-fibers is apparent 1 day after incision. Because sensitization of afferent fibers to mechanical stimuli correlated with behavioral results, sensitization may contribute to the reduced withdrawal threshold after incision. Spontaneous activity in Aδ- and C-fibers may account for nonevoked pain behavior and may also contribute to mechanical hyperalgesia by amplifying responses centrally.

scholarly journals Peripheral Contributions to Visceral Hyperalgesia

1999 ◽  
Vol 13 (suppl a) ◽  
pp. 37A-41A ◽  
Author(s):  
GF Gebhart
Keyword(s):  
Spinal Cord ◽  
Urinary Bladder ◽  
Tissue Injury ◽  
Mechanical Stimuli ◽  
Sensory Receptors ◽  
Visceral Hyperalgesia ◽  
Nonhuman Animals ◽  
Primary Hyperalgesia ◽  
Thermal Stimuli ◽  
Key Questions

Hyperalgesia has long been recognized clinically as a consequence of tissue injury. Primary hyperalgesia (arising from the site of injury) is generally considered to be due to sensitization of sensory receptors (eg, nociceptors) and perhaps activation of so-called ‘silent nociceptors’ by mediators released, synthesized or attracted to the site of tissue injury. Key questions associated with understanding visceral hyperalgesia relate to whether the viscera are innervated by nociceptors (ie, sensory receptors that respond selectively to noxious intensities of stimulation), whether visceral receptors and/or afferent fibres sensitize after tissue injury and whether silent nociceptors exist in the viscera. Studies in nonhuman animals have revealed that hollow organs such as the esophagus, gall bladder, stomach, urinary bladder, colon and uterus are innervated by mechanically sensitive receptors with low or high thresholds for response. Accordingly, it appears that the viscera are innervated by nociceptors, although the issue is far from settled. One characteristic of cutaneous nociceptors is their ability to be sensitized when tissue is injured. Mechanosensitive visceral receptors also sensitize when the viscera are experimentally inflamed, but both visceral receptors with low thresholds and those with high thresholds for response are sensitized. Moreover, it is often not appreciated that visceral receptors are likely polymodal rather than unimodal – that is, mechanically sensitive visceral receptors typically are also sensitive to chemical and/or thermal stimuli. In this sense, visceral receptors may be considered evolutionarily older than more highly developed, specialized cutaneous receptors. Finally, there are mechanically insensitive receptors that innervate the viscera and, when tissue is injured, develop spontaneous activity and acquire sensitivity to mechanical stimuli. In the aggregrate, visceral receptors change their behaviour in the presence of tissue injury and, along with activated mechanically insensitive receptors, increase the afferent barrage into the spinal cord, contributing to the development of visceral hyperalgesia.

Neural Processing of Pain and Itch

2021 ◽  
Author(s):  
Taylor Follansbee ◽  
Mirela Iodi Carstens ◽  
E. Carstens
Keyword(s):  
Central Sensitization ◽  
Tissue Injury ◽  
Emotional Experience ◽  
Spinal Pain ◽  
Anterior Cingulate ◽  
Mechanical Stimuli ◽  
Firing Rates ◽  
Spinal Circuitry ◽  
Ascending Pathways ◽  
Primary Hyperalgesia

Pain is defined as “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage,” while itch can be defined as “an unpleasant sensation that evokes the desire to scratch.” These sensations are normally elicited by noxious or pruritic stimuli that excite peripheral sensory neurons connected to spinal circuits and ascending pathways involved in sensory discrimination, emotional aversiveness, and respective motor responses. Specialized molecular receptors expressed by cutaneous nerve endings transduce stimuli into action potentials conducted by C- and Aδ-fiber nociceptors and pruriceptors into the outer lamina of the dorsal horn of the spinal cord. Here, neurons selectively activated by nociceptors, or by convergent input from nociceptors, pruriceptors, and often mechanoreceptors, transmit signals to ascending spinothalamic and spinoparabrachial pathways. The spinal circuitry for itch requires interneurons expressing gastrin-releasing peptide and its receptor, while spinal pain circuitry involves other excitatory neuropeptides; both itch and pain are transmitted by ascending pathways that express the receptor for substance P. Spinal itch- and pain-transmitting circuitry is segmentally modulated by inhibitory interneurons expressing dynorphin, GABA, and glycine, which mediate the antinociceptive and antipruritic effects of noxious counterstimulation. Spinal circuits are also under descending modulation from the brainstem rostral ventromedial medulla. Opioids like morphine inhibit spinal pain-transmitting circuits segmentally and via descending inhibitory pathways, while having the opposite effect on itch. The supraspinal targets of ascending pain and itch pathways exhibit extensive overlap and include the somatosensory thalamus, parabrachial nucleus, amygdala, periaqueductal gray, and somatosensory, anterior cingulate, insular, and supplementary motor cortical areas. Following tissue injury, enhanced pain is evoked near the injury (primary hyperalgesia) due to release of inflammatory mediators that sensitize nociceptors. Within a larger surrounding area of secondary hyperalgesia, innocuous mechanical stimuli elicit pain (allodynia) due to central sensitization of pain pathways. Pruriceptors can also become sensitized in pathophysiological conditions, such as dermatitis. Under chronic itch conditions, low-threshold tactile stimulation can elicit itch (alloknesis), presumably due to central sensitization of itch pathways, although this has not been extensively studied. There is considerable overlap in pain- and itch-signaling pathways and it remains unclear how these sensations are discriminated. Specificity theory states that itch and pain are separate sensations with their own distinct pathways (“labeled lines”). Selectivity theory is similar but incorporates the observation that pruriceptive neurons are also excited by algogenic stimuli that inhibit spinal itch transmission. In contrast, intensity theory states that itch is signaled by low firing rates, and pain by high firing rates, in a common sensory pathway. Finally, the spatial contrast theory proposes that itch is elicited by focal activation of a few nociceptors while activation of more nociceptors over a larger area elicits pain. There is evidence supporting each theory, and it remains to be determined how the nervous system distinguishes between pain and itch.

Nociceptive signalling in the periphery and spinal cord

2013 ◽  
pp. 53-64
Author(s):  
Suellen M. Walker ◽  
Mark L. Baccei
Keyword(s):  
Spinal Cord ◽  
Tissue Injury ◽  
Afferent Input ◽  
Acute Response ◽  
Management Interventions ◽  
Age Related ◽  
Noxious Stimuli ◽  
Electrical Stimuli ◽  
Age Related Changes

Responses to painful or noxious stimuli are functional at birth. However, postnatal changes in the transmitters, receptors, and pathways involved in nociceptive signalling result in significant age-related changes in the nature and degree of response. Noxious mechanical, thermal, and chemical stimuli are detected by peripheral nociceptors, transduced into electrical stimuli, and transmitted to the spinal cord. Within the spinal cord, there are significant postnatal changes in the balance of inhibitory and excitatory signalling, that not only influence the acute response to afferent input, but can also underlie long-term alterations in sensory processing following tissue injury in early life. Evaluating age-related changes in nociceptive signalling is essential not only for understanding acute behavioural responses to noxious stimuli, but also for identifying the most appropriate and effective pain management interventions at different developmental ages.

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