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  1. Article: Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation.

    Lubejko, Susan T / Livrizzi, Giulia / Patel, Janki / Yung, Jean C / Yaksh, Tony L / Banghart, Matthew R

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, ... ...

    Abstract The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, we establish that noradrenergic neurons of the locus coeruleus (LC) are essential for supraspinal opioid antinociception. Unexpectedly, given prior emphasis on descending serotonergic pathways, we find that opioid antinociception is primarily driven by excitatory output from the ventrolateral periaqueductal gray (vlPAG) to the LC. Furthermore, we identify a previously unknown opioid-sensitive inhibitory input from the rostroventromedial medulla (RVM), the suppression of which disinhibits LC neurons to drive spinal noradrenergic antinociception. We also report the presence of prominent bifurcating outputs from the vlPAG to the LC and the RVM. Our findings significantly revise current models of the DPMS and establish a novel supraspinal antinociceptive pathway that may contribute to multiple forms of descending pain modulation.
    Language English
    Publishing date 2023-10-10
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.10.561768
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Inputs to the locus coeruleus from the periaqueductal gray and rostroventral medulla shape opioid-mediated descending pain modulation.

    Lubejko, Susan T / Livrizzi, Giulia / Buczynski, Stanley A / Patel, Janki / Yung, Jean C / Yaksh, Tony L / Banghart, Matthew R

    Science advances

    2024  Volume 10, Issue 17, Page(s) eadj9581

    Abstract: The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, ... ...

    Abstract The supraspinal descending pain modulatory system (DPMS) shapes pain perception via monoaminergic modulation of sensory information in the spinal cord. However, the role and synaptic mechanisms of descending noradrenergic signaling remain unclear. Here, we establish that noradrenergic neurons of the locus coeruleus (LC) are essential for supraspinal opioid antinociception. While much previous work has emphasized the role of descending serotonergic pathways, we find that opioid antinociception is primarily driven by excitatory output from the ventrolateral periaqueductal gray (vlPAG) to the LC. Furthermore, we identify a previously unknown opioid-sensitive inhibitory input from the rostroventromedial medulla (RVM), the suppression of which disinhibits LC neurons to drive spinal noradrenergic antinociception. We describe pain-related activity throughout this circuit and report the presence of prominent bifurcating outputs from the vlPAG to the LC and the RVM. Our findings substantially revise current models of the DPMS and establish a supraspinal antinociceptive pathway that may contribute to multiple forms of descending pain modulation.
    MeSH term(s) Locus Coeruleus/metabolism ; Locus Coeruleus/drug effects ; Periaqueductal Gray/metabolism ; Periaqueductal Gray/drug effects ; Animals ; Medulla Oblongata/metabolism ; Medulla Oblongata/drug effects ; Pain/drug therapy ; Pain/metabolism ; Analgesics, Opioid/pharmacology ; Male ; Adrenergic Neurons/metabolism ; Adrenergic Neurons/drug effects ; Mice ; Neural Pathways/drug effects
    Chemical Substances Analgesics, Opioid
    Language English
    Publishing date 2024-04-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.adj9581
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  3. Article: 12/15-Lipoxygenases mediate neuropathic-like pain hypersensitivity in female mice.

    Brown, B / Chen, I / Miliano, C / Murdaugh, L B / Dong, Y / Eddinger, K A / Yaksh, T L / Burton, M D / Buczynski, M W / Gregus, A M

    bioRxiv : the preprint server for biology

    2024  

    Abstract: It is estimated that chronic neuropathic pain conditions exhibit up to 10% prevalence in the general population, with increased incidence in females. However, nonsteroidal inflammatory drugs (NSAIDs) are ineffective, and currently indicated prescription ... ...

    Abstract It is estimated that chronic neuropathic pain conditions exhibit up to 10% prevalence in the general population, with increased incidence in females. However, nonsteroidal inflammatory drugs (NSAIDs) are ineffective, and currently indicated prescription treatments such as opioids, anticonvulsants, and antidepressants provide only limited therapeutic benefit. In the current work, we extended previous studies in male rats utilizing a paradigm of central Toll-like receptor 4 (TLR4)-dependent, NSAID-unresponsive neuropathic-like pain hypersensitivity to male and female C57BL/6N mice, uncovering an unexpected hyperalgesic phenotype in female mice following intrathecal (IT) LPS. In contrast to previous reports in female C57BL/6J mice, female C57BL/6N mice displayed tactile and cold allodynia, grip force deficits, and locomotor hyperactivity in response to IT LPS. Congruent with our previous observations in male rats, systemic inhibition of 12/15-Lipoxygenases (12/15-LOX) in female B6N mice with selective inhibitors - ML355 (targeting 12-LOX-p) and ML351 (targeting 15-LOX-1) - completely reversed allodynia and grip force deficits. We demonstrate here that 12/15-LOX enzymes also are expressed in mouse spinal cord and that 12/15-LOX metabolites produce tactile allodynia when administered spinally (IT) or peripherally (intraplantar in the paw, IPLT) in a hyperalgesic priming model, similar to others observations with the cyclooxygenase (COX) metabolite Prostaglandin E
    Language English
    Publishing date 2024-04-08
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.04.588153
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  4. Article ; Online: Severe altered mentation due to cervicothoracic intrathecal pump after correction of cervical stenosis: a case report.

    Sanghvi, Chinar / Su, Tiffany / Yaksh, Tony L / Copenhaver, David J / Klineberg, Eric O / Jung, Michael J

    Regional anesthesia and pain medicine

    2021  Volume 46, Issue 12, Page(s) 1100–1102

    Abstract: Background: Cerebral spinal fluid (CSF) dynamics are complex and changes in spinal anatomy may influence the rostrocaudal movement of intrathecal medications. We present the first reported case demonstrating that acute cervical spinal stenosis may ... ...

    Abstract Background: Cerebral spinal fluid (CSF) dynamics are complex and changes in spinal anatomy may influence the rostrocaudal movement of intrathecal medications. We present the first reported case demonstrating that acute cervical spinal stenosis may impede the distribution of adjacent intrathecal medications, and that correction of such stenosis and the resulting changes in CSF flow may necessitate significant adjustments in the intrathecal infusates.
    Case presentation: We present a case of a 60-year-old male patient with a cervicothoracic intrathecal pump (ITP) infusing morphine, bupivacaine, and baclofen for chronic neck pain. The alert and oriented patient had a recent fall resulting in an acute severe cervical stenosis and cord compression which required urgent surgical decompression. Postoperatively, after the cervical decompression, the patient had significant altered mental status requiring a naloxone infusion. Multiple attempts to reduce the naloxone infusion were initially not successful due to worsened somnolence. The previously tolerated ITP medications were continuously reduced over the next 14 days, allowing concomitant decrease and eventual cessation of the naloxone infusion while maintaining patient mental status. The only opioids the patient received during this period were from the ITP.
    Conclusions: This case presents clinical evidence that severe spinal stenosis may impede the rostral CSF distribution of intrathecal medications. Intrathecal medications previously tolerated by patients prior to decompression may need to be significantly reduced in the postoperative period.
    MeSH term(s) Analgesics, Opioid/therapeutic use ; Bupivacaine/therapeutic use ; Cervical Vertebrae/diagnostic imaging ; Cervical Vertebrae/surgery ; Constriction, Pathologic/drug therapy ; Humans ; Injections, Spinal ; Male ; Middle Aged ; Morphine/therapeutic use ; Naloxone/therapeutic use ; Spinal Stenosis/complications ; Spinal Stenosis/diagnostic imaging
    Chemical Substances Analgesics, Opioid ; Naloxone (36B82AMQ7N) ; Morphine (76I7G6D29C) ; Bupivacaine (Y8335394RO)
    Language English
    Publishing date 2021-09-06
    Publishing country England
    Document type Case Reports ; Journal Article
    ZDB-ID 1425299-5
    ISSN 1532-8651 ; 1098-7339 ; 0146-521X
    ISSN (online) 1532-8651
    ISSN 1098-7339 ; 0146-521X
    DOI 10.1136/rapm-2021-103041
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  5. Article ; Online: Pain mechanisms in the transgender individual: a review.

    Anger, Jennifer T / Case, Laura K / Baranowski, Andrew P / Berger, Ardin / Craft, Rebecca M / Damitz, Lyn Ann / Gabriel, Rodney / Harrison, Tracy / Kaptein, Kirsten / Lee, Sanghee / Murphy, Anne Z / Said, Engy / Smith, Stacey Abigail / Thomas, David A / Valdés Hernández, Maria Del C / Trasvina, Victor / Wesselmann, Ursula / Yaksh, Tony L

    Frontiers in pain research (Lausanne, Switzerland)

    2024  Volume 5, Page(s) 1241015

    Abstract: Specific aim: Provide an overview of the literature addressing major areas pertinent to pain in transgender persons and to identify areas of primary relevance for future research.: Methods: A team of scholars that have previously published on ... ...

    Abstract Specific aim: Provide an overview of the literature addressing major areas pertinent to pain in transgender persons and to identify areas of primary relevance for future research.
    Methods: A team of scholars that have previously published on different areas of related research met periodically though zoom conferencing between April 2021 and February 2023 to discuss relevant literature with the goal of providing an overview on the incidence, phenotype, and mechanisms of pain in transgender patients. Review sections were written after gathering information from systematic literature searches of published or publicly available electronic literature to be compiled for publication as part of a topical series on gender and pain in the Frontiers in Pain Research.
    Results: While transgender individuals represent a significant and increasingly visible component of the population, many researchers and clinicians are not well informed about the diversity in gender identity, physiology, hormonal status, and gender-affirming medical procedures utilized by transgender and other gender diverse patients. Transgender and cisgender people present with many of the same medical concerns, but research and treatment of these medical needs must reflect an appreciation of how differences in sex, gender, gender-affirming medical procedures, and minoritized status impact pain.
    Conclusions: While significant advances have occurred in our appreciation of pain, the review indicates the need to support more targeted research on treatment and prevention of pain in transgender individuals. This is particularly relevant both for gender-affirming medical interventions and related medical care. Of particular importance is the need for large long-term follow-up studies to ascertain best practices for such procedures. A multi-disciplinary approach with personalized interventions is of particular importance to move forward.
    Language English
    Publishing date 2024-03-27
    Publishing country Switzerland
    Document type Journal Article ; Review
    ISSN 2673-561X
    ISSN (online) 2673-561X
    DOI 10.3389/fpain.2024.1241015
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  6. Article: Neonates have a spinal alpha receptor too, as do adults.

    Yaksh, T L

    British journal of pharmacology

    2007  Volume 151, Issue 8, Page(s) 1139–1140

    MeSH term(s) Adrenergic alpha-Agonists/administration & dosage ; Adrenergic alpha-Agonists/adverse effects ; Adrenergic alpha-Agonists/pharmacology ; Adult ; Age Factors ; Analgesics/administration & dosage ; Analgesics/adverse effects ; Analgesics/pharmacology ; Animals ; Animals, Newborn ; Dexmedetomidine/administration & dosage ; Dexmedetomidine/adverse effects ; Dexmedetomidine/pharmacology ; Humans ; Infant, Newborn ; Injections, Spinal ; Pain/drug therapy ; Pain/physiopathology ; Pain Measurement ; Pain Threshold ; Phenotype ; Rats ; Receptors, Adrenergic, alpha/drug effects ; Receptors, Adrenergic, alpha/physiology ; Species Specificity
    Chemical Substances Adrenergic alpha-Agonists ; Analgesics ; Receptors, Adrenergic, alpha ; Dexmedetomidine (67VB76HONO)
    Language English
    Publishing date 2007-08
    Publishing country England
    Document type Comment ; Journal Article
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1038/sj.bjp.0707291
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  7. Article: Unintended consequences of COVID-19 safety measures on patients with chronic knee pain forced to defer joint replacement surgery

    Cisternas, A. F. / Ramachandran, R. / Yaksh, T. L. / Nahama, A.

    Pain Rep

    Abstract: In recent months, with the emergence of the COVID-19 pandemic, the American College of Surgeons and the U S Centers for Disease Control and Prevention officially recommended the delay of nonemergency procedures until the public health crisis is resolved ... ...

    Abstract In recent months, with the emergence of the COVID-19 pandemic, the American College of Surgeons and the U S Centers for Disease Control and Prevention officially recommended the delay of nonemergency procedures until the public health crisis is resolved Deferring elective joint replacement surgeries for an unknown period is likely to decrease the incidence of infection with SARS-CoV-2 but is likely to have detrimental effects in individuals suffering from chronic knee pain These detrimental effects extend beyond the discomfort of osteoarthritis (OA) and the inconvenience of rescheduling surgery Disabling pain is a driving factor for individuals to seek medical intervention, including pharmacological palliative treatment and surgical procedures The need for surgical intervention due to chronic pain as for knee and hip replacement is now put on hold indefinitely because access to surgical care has been limited Although a moderate delay in surgical intervention may not produce a significant progression of OA within the knee, it could lead to muscle wasting due to immobility and exacerbate comorbidities, making rehabilitation more challenging Importantly, it will have an impact on comorbidities driven by OA severity, notably decreased quality of life and depression These patients with unremitting pain become increasingly susceptible to substance use disorders including opioids, alcohol, as well as prescription and illegal drugs Appreciation of this downstream crisis created by delayed surgical correction requires aggressive consideration of nonsurgical, nonopiate supported interventions to reduce the morbidity associated with these delays brought upon by the currently restricted access to joint repair
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #900676
    Database COVID19

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  8. Article ; Online: Differences in cisplatin-induced mechanical allodynia in male and female mice.

    Woller, S A / Corr, M / Yaksh, T L

    European journal of pain (London, England)

    2015  Volume 19, Issue 10, Page(s) 1476–1485

    Abstract: Background: Chemotherapeutic agents, such as cisplatin, are known to induce a persistent polyneuropathy. The mechanisms underlying the development of this pain are complex, and have only been investigated rodent models using male animals, despite an ... ...

    Abstract Background: Chemotherapeutic agents, such as cisplatin, are known to induce a persistent polyneuropathy. The mechanisms underlying the development of this pain are complex, and have only been investigated rodent models using male animals, despite an equivalent presentation of neuropathy between the sexes, clinically.
    Methods: Male and female C57Bl/6, Tlr3(-/-) Tlr4(-/-) , Myd88(-/-) , Trif(lps2) and Myd88(-/-) /Trif(lps2) mice received 6 i.p. injections of cisplatin (2.3 mg/kg/day) every other day over the course of 2 weeks. Changes in tactile threshold were monitored during this time, continuing through day 23, using von Frey filaments.
    Results: Male WT mice develop a persistent tactile allodynia resulting from cisplatin administration. Female mice develop an initial allodynia, but thresholds return to baseline by day 23. Deletion of TLR3, TLR4, MyD88 and Trif/MyD88 protects animals from the development of cisplatin-induced polyneuropathy, and there are no sex differences. Trif(lps2) male mice show a persistent tactile allodynia following cisplatin administration, while female mice show a reduced allodynia, and remain higher in threshold than their male counterparts. On day 18, animals were given the analgesic gabapentin, and thresholds were tested 45 min after. Gabapentin was effective in transiently reversing mechanical allodynia in those mice with lowered thresholds.
    Conclusions: It is important to continue examining both sexes in various pain models, as a mononeuropathy and polyneuropathy show sex differences in pain development and the role of TLR signalling.
    MeSH term(s) Amines/administration & dosage ; Amines/pharmacology ; Analgesics/administration & dosage ; Analgesics/pharmacology ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/toxicity ; Cisplatin/administration & dosage ; Cisplatin/toxicity ; Cyclohexanecarboxylic Acids/administration & dosage ; Cyclohexanecarboxylic Acids/pharmacology ; Disease Models, Animal ; Female ; Hyperalgesia/chemically induced ; Hyperalgesia/drug therapy ; Hyperalgesia/etiology ; Male ; Mice ; Mice, Inbred C57BL ; Mononeuropathies/chemically induced ; Mononeuropathies/complications ; Neuralgia/chemically induced ; Neuralgia/drug therapy ; Neuralgia/etiology ; Pain Threshold/drug effects ; Polyneuropathies/chemically induced ; Polyneuropathies/complications ; Sex Factors ; Signal Transduction/drug effects ; Toll-Like Receptors/metabolism ; gamma-Aminobutyric Acid/administration & dosage ; gamma-Aminobutyric Acid/pharmacology
    Chemical Substances Amines ; Analgesics ; Antineoplastic Agents ; Cyclohexanecarboxylic Acids ; Toll-Like Receptors ; gamma-Aminobutyric Acid (56-12-2) ; gabapentin (6CW7F3G59X) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2015-11
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1390424-3
    ISSN 1532-2149 ; 1090-3801
    ISSN (online) 1532-2149
    ISSN 1090-3801
    DOI 10.1002/ejp.679
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    Zs.A 5194: Show issues Location:
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  9. Article ; Online: Treating osteoarthritis pain: mechanisms of action of acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, and nerve growth factor antibodies.

    D'Arcy, Yvonne / Mantyh, Patrick / Yaksh, Tony / Donevan, Sean / Hall, Jerry / Sadrarhami, Mojgan / Viktrup, Lars

    Postgraduate medicine

    2021  Volume 133, Issue 8, Page(s) 879–894

    Abstract: Osteoarthritis (OA) is a common difficult-to-treat condition where the goal, in the absence of disease-modifying treatments, is to alleviate symptoms such as pain and loss of function. Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and ... ...

    Abstract Osteoarthritis (OA) is a common difficult-to-treat condition where the goal, in the absence of disease-modifying treatments, is to alleviate symptoms such as pain and loss of function. Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids are common pharmacologic treatments for OA. Antibodies directed against nerve growth factor (NGF-Abs) are a new class of agents under clinical investigation for the treatment of OA. This narrative review describes (and uses schematics to visualize) nociceptive signaling, chronification of pain, and the mechanisms of action (MOAs) of these different analgesics in the context of OA-related pain pathophysiology. Further, the varying levels of efficacy and safety of these agents observed in patients with OA is examined, based on an overview of published clinical data and/or treatment guidelines (when available), in the context of differences in their MOAs.
    MeSH term(s) Acetaminophen/therapeutic use ; Analgesics, Non-Narcotic/therapeutic use ; Analgesics, Opioid/therapeutic use ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Osteoarthritis/drug therapy ; Pain Management
    Chemical Substances Analgesics, Non-Narcotic ; Analgesics, Opioid ; Anti-Inflammatory Agents, Non-Steroidal ; Acetaminophen (362O9ITL9D)
    Language English
    Publishing date 2021-07-12
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 410138-8
    ISSN 1941-9260 ; 0032-5481
    ISSN (online) 1941-9260
    ISSN 0032-5481
    DOI 10.1080/00325481.2021.1949199
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  10. Article ; Online: Regulation of spinal substance p release by intrathecal calcium channel blockade.

    Takasusuki, Toshifumi / Yaksh, Tony L

    Anesthesiology

    2011  Volume 115, Issue 1, Page(s) 153–164

    Abstract: ... emphasize the role in vivo of N-type but not T- and L-type voltage-sensitive calcium channel blockers ... in mediating the stimulus-evoked substance P release from small primary afferents and suggest that T- and L ... by intraplantar formalin by examining the effects of intrathecally delivered N- (ziconotide), T- (mibefradil), and ...

    Abstract Background: The authors investigated the role of different voltage-sensitive calcium channels expressed at presynaptic afferent terminals in substance P release and on nociceptive behavior evoked by intraplantar formalin by examining the effects of intrathecally delivered N- (ziconotide), T- (mibefradil), and L-type voltage-sensitive calcium channel blockers (diltiazem and verapamil).
    Methods: Rats received intrathecal pretreatment with saline or doses of morphine, ziconotide, mibefradil, diltiazem, or verapamil. The effect of these injections upon flinching evoked by intraplantar formalin (5%, 50 μl) was quantified. To assess substance P release, the incidence of neurokinin-1 receptor internalization in the ipsilateral and contralateral lamina I was determined in immunofluorescent-stained tissues.
    Results: Intrathecal morphine (20 μg), ziconotide (0.3, 0.6, and 1 μg), mibefradil (100 μg, but not 50 μg), diltiazem (500 μg, but not 300 μg), and verapamil (200 μg, but not 50 and 100 μg) reduced paw flinching in phase 2 compared with vehicle control (P < 0.05), with no effect on phase 1. Ziconotide (0.3, 0.6, and 1 μg) and morphine (20 μg) significantly inhibited neurokinin-1 receptor internalization (P < 0.05), but mibefradil, diltiazem, and verapamil at the highest doses had no effect.
    Conclusion: These results emphasize the role in vivo of N-type but not T- and L-type voltage-sensitive calcium channel blockers in mediating the stimulus-evoked substance P release from small primary afferents and suggest that T- and L-type voltage-sensitive calcium channel blockers exert antihyperalgesic effects by an action on other populations of afferents or mechanisms involving postsynaptic excitability.
    MeSH term(s) Analgesics, Opioid/pharmacology ; Animals ; Behavior, Animal/drug effects ; Calcium Channel Blockers/administration & dosage ; Calcium Channel Blockers/pharmacology ; Calcium Channels, L-Type/drug effects ; Calcium Channels, N-Type/drug effects ; Calcium Channels, T-Type/drug effects ; Dose-Response Relationship, Drug ; Immunohistochemistry ; Injections, Spinal ; Male ; Morphine/pharmacology ; Movement/drug effects ; Pain Measurement ; Posterior Horn Cells/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Neurokinin-1/drug effects ; Spinal Cord/drug effects ; Spinal Cord/metabolism ; Substance P/metabolism ; omega-Conotoxins/administration & dosage ; omega-Conotoxins/pharmacology
    Chemical Substances Analgesics, Opioid ; Calcium Channel Blockers ; Calcium Channels, L-Type ; Calcium Channels, N-Type ; Calcium Channels, T-Type ; Receptors, Neurokinin-1 ; omega-Conotoxins ; Substance P (33507-63-0) ; Morphine (76I7G6D29C) ; ziconotide (7I64C51O16)
    Language English
    Publishing date 2011-06-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 269-0
    ISSN 1528-1175 ; 0003-3022
    ISSN (online) 1528-1175
    ISSN 0003-3022
    DOI 10.1097/ALN.0b013e31821950c2
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