Placing pain on the sensory map: Classic papers by Ed Perl and colleagues

This essay looks at two papers published by Ed Perl and co-workers that identified specifically nociceptive neurons in the periphery and superficial dorsal horn. Bessou P and Perl ER. Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli. J Neurophysiol 32: 1025–1043 1969. Christensen BN and Perl ER. Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn. J Neurophysiol 33: 293–307 1970.

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Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn.

Journal of Neurophysiology ◽

10.1152/jn.1970.33.2.293 ◽

1970 ◽

Vol 33 (2) ◽

pp. 293-307 ◽

Cited By ~ 522

Author(s):

B N Christensen ◽

E R Perl

Keyword(s):

Dorsal Horn ◽

Marginal Zone ◽

Spinal Neurons ◽

Thermal Stimuli

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Grouping of somatosensory neurons in the spinal cord and the gracile nucleus of the rat by cluster analysis

Journal of Neurophysiology ◽

10.1152/jn.1994.72.6.2590 ◽

1994 ◽

Vol 72 (6) ◽

pp. 2590-2597 ◽

Cited By ~ 20

Author(s):

J. W. Leem ◽

B. H. Lee ◽

W. D. Willis ◽

J. M. Chung

Keyword(s):

Cluster Analysis ◽

Dorsal Horn ◽

Dynamic Range ◽

High Threshold ◽

Spinothalamic Tract ◽

Wide Dynamic Range ◽

Gracile Nucleus ◽

Noxious Stimuli ◽

Thermal Stimuli ◽

Wide Dynamic Range Neurons

1. A set of 11 cutaneous stimuli defined previously to differentiate among different types of cutaneous sensory receptors in the rat hindpaw was also effective in differentially activating second-order sensory neurons in the dorsal horn and the gracile nucleus of rats. 2. All sampled units were responsive to more than 1 of the 11 stimuli. However, none responded to innocuous warming or cooling stimuli. Therefore further analysis was restricted to responses to nine of the selected stimuli. 3. Cluster analysis of the responses to nine selected innocuous and noxious mechanical stimuli and noxious thermal stimuli yielded seven classes that seemed functionally distinct from each other: a class of high-threshold neurons, three classes of convergent (wide dynamic range) neurons, a class of a mixture of poorly responsive neurons and neurons receiving Pacinian inputs, and two classes of low-threshold neurons. 4. High-threshold neurons responded predominantly to noxious mechanical and thermal stimuli and presumably received an input from both mechanically and thermally sensitive nociceptors. These cells were located in the dorsal horn, and some were spinothalamic tract cells. Wide dynamic range neurons were excited by innocuous and noxious stimuli, but better by noxious stimuli. These classes of cells were either in the dorsal horn (some were spinothalamic tract cells) or in the nucleus gracilis.(ABSTRACT TRUNCATED AT 250 WORDS)

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α2-Adrenoceptors Modulate NMDA-Evoked Responses of Neurons in Superficial and Deeper Dorsal Horn of the Medulla

Journal of Neurophysiology ◽

10.1152/jn.1998.80.4.2210 ◽

1998 ◽

Vol 80 (4) ◽

pp. 2210-2214 ◽

Cited By ~ 16

Author(s):

Kai-Ming Zhang ◽

Xiao-Min Wang ◽

Angela M. Peterson ◽

Wen-Yan Chen ◽

Sukhbir S. Mokha

Keyword(s):

Dorsal Horn ◽

Dynamic Range ◽

Inhibitory Effect ◽

Male Rats ◽

Evoked Responses ◽

Superficial Dorsal Horn ◽

Nociceptive Neurons ◽

Adrenoceptor Antagonist ◽

Medullary Dorsal Horn ◽

Wdr Neurons

Kai-Ming Zhang, Xiao-Min Wang, Angela M. Peterson, Wen-Yan Chen, and Sukhbir S. Mokha. α2-Adrenoceptors modulate NMDA-evoked responses of neurons in the superficial and deeper dorsal horn of the medulla. J. Neurophysiol. 80: 2210–2214, 1998. Extracellular single unit recordings were made from neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in 21 male rats anesthetized with urethan. NMDA produced an antagonist-reversible excitation of 46 nociceptive as well as nonnociceptive neurons. Microiontophoretic application of a preferential α2-adrenoceptor (α2AR) agonist, (2-[2,6-dichloroaniline]-2-imidazoline) hydrochloride (clonidine), reduced the NMDA-evoked responses of 86% (6/7) of nociceptive-specific (NS) neurons, 82% (9/11) of wide dynamic range (WDR) neurons, and 67% (4/6) of low-threshold (LT) neurons in the superficial dorsal horn. In the deeper dorsal horn, clonidine inhibited the NMDA-evoked responses of 94% (16/17) of NS and WDR neurons and 60% (3/5) of LT neurons. Clonidine facilitated the NMDA-evoked responses in 14% (1/17) of NS, 9% (1/11) of WDR, and 33% (2/6) of LT neurons in the superficial dorsal horn. Idazoxan, an α2AR antagonist, reversed the inhibitory effect of clonidine in 90% (9/10) of neurons, whereas prazosin, an α1-adrenoceptor antagonist with affinity for α2BAR, and α2CAR, were ineffective. We suggest that activation of α2ARs produces a predominantly inhibitory modulation of the NMDA-evoked responses of nociceptive neurons in the medullary dorsal horn.

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9. Small nociceptive neurons in the superficial dorsal horn of the cat

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1985.0049 ◽

1985 ◽

Vol 308 (1136) ◽

pp. 415-415

Keyword(s):

Horseradish Peroxidase ◽

Dorsal Horn ◽

Morphological Features ◽

Superficial Dorsal Horn ◽

Afferent Stimulation ◽

Nociceptive Neurons ◽

Dorsal Horn Neurons ◽

Lamina I ◽

Stimulation Of

Horseradish peroxidase (HRP) staining of superficial dorsal horn neurons with identified inputs from the skin has shown a population of nociceptive Waldeyer neurones in lamina I and also a population of neurons with small perikarya situated close to the lamina I/II border (Rethelyi et al. 1983). We have studied morphological features and responses to afferent stimulation of these latter neurons.

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Fentanyl Suppression of Nociceptive Neurons in the Superficial Dorsal Horn of the Cat

Anesthesiology ◽

10.1097/00000542-198809000-00014 ◽

1988 ◽

Vol 69 (3) ◽

pp. 371-376 ◽

Cited By ~ 8

Author(s):

Yukihiro Kumeta ◽

Kenji Murata ◽

Luke M. Kitahata ◽

Mitsuru Aoki ◽

Yuji Nishio ◽

...

Keyword(s):

Dorsal Horn ◽

Superficial Dorsal Horn ◽

Nociceptive Neurons

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Inflammation and hyperalgesia in rats neonatally treated with capsaicin: effects on two classes of nociceptive neurons in the superficial dorsal horn

Pain ◽

10.1016/0304-3959(94)90082-5 ◽

1994 ◽

Vol 59 (2) ◽

pp. 287-300 ◽

Cited By ~ 35

Author(s):

Ke Ren ◽

Gene M. Williams ◽

M. A. Ruda ◽

Ronald Dubner

Keyword(s):

Dorsal Horn ◽

Superficial Dorsal Horn ◽

Nociceptive Neurons

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Intradermal endothelin-1 excites bombesin-responsive superficial dorsal horn neurons in the mouse

Journal of Neurophysiology ◽

10.1152/jn.00723.2015 ◽

2015 ◽

Vol 114 (4) ◽

pp. 2528-2534 ◽

Cited By ~ 4

Author(s):

T. Akiyama ◽

M. Nagamine ◽

A. Davoodi ◽

M. Iodi Carstens ◽

F. Cevikbas ◽

...

Keyword(s):

Dorsal Horn ◽

Dynamic Range ◽

Allyl Isothiocyanate ◽

High Threshold ◽

Mechanical Stimuli ◽

Superficial Dorsal Horn ◽

Noxious Heat ◽

Nociceptive Neurons ◽

Endothelin 1 ◽

Dorsal Horn Neurons

Endothelin-1 (ET-1) has been implicated in nonhistaminergic itch. Here we used electrophysiological methods to investigate whether mouse superficial dorsal horn neurons respond to intradermal (id) injection of ET-1 and whether ET-1-sensitive neurons additionally respond to other pruritic and algesic stimuli or spinal superfusion of bombesin, a homolog of gastrin-releasing peptide (GRP) that excites spinal itch-signaling neurons. Single-unit recordings were made from lumbar dorsal horn neurons in pentobarbital-anesthetized C57BL/6 mice. We searched for units that exhibited elevated firing after id injection of ET-1 (1 μg/μl). Responsive units were further tested with mechanical stimuli, bombesin (spinal superfusion, 200 μg·ml−1·min−1), heating, cooling, and additional chemicals [histamine, chloroquine, allyl isothiocyanate (AITC), capsaicin]. Of 40 ET-1-responsive units, 48% responded to brush and pinch [wide dynamic range (WDR)] and 52% to pinch only [high threshold (HT)]. Ninety-three percent responded to noxious heat, 50% to cooling, and >70% to histamine, chloroquine, AITC, and capsaicin. Fifty-seven percent responded to bombesin, suggesting that they participate in spinal itch transmission. That most ET-1-sensitive spinal neurons also responded to pruritic and algesic stimuli is consistent with previous studies of pruritogen-responsive dorsal horn neurons. We previously hypothesized that pruritogen-sensitive neurons signal itch. The observation that ET-1 activates nociceptive neurons suggests that both itch and pain signals may be generated by ET-1 to result in simultaneous sensations of itch and pain, consistent with observations that ET-1 elicits both itch- and pain-related behaviors in animals and burning itch sensations in humans.

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Spinal Neurons That Express NK-1 Receptors Modulate Descending Controls That Project Through the Dorsolateral Funiculus

Journal of Neurophysiology ◽

10.1152/jn.01160.2003 ◽

2005 ◽

Vol 93 (2) ◽

pp. 998-1006 ◽

Cited By ~ 25

Author(s):

Sergey G. Khasabov ◽

Joseph R. Ghilardi ◽

Patrick W. Mantyh ◽

Donald A. Simone

Keyword(s):

Substance P ◽

Spontaneous Activity ◽

Dorsal Horn ◽

Spinal Neurons ◽

Nociceptive Neurons ◽

Dorsal Horn Neurons ◽

Before And After ◽

Descending Systems ◽

Dorsolateral Funiculus ◽

Evoked Activity

Selective ablation of spinal neurons possessing substance P receptors (NK-1 receptors) using the selective cytotoxin conjugate substance P-saporin (SP-SAP) decreases hyperalgesia and central sensitization. The mechanisms by which NK-1 expressing neurons modulate the excitability of other dorsal horn neurons are unclear. Because the majority of NK-1 expressing spinal neurons project rostrally, it is possible that they are part of a spinal-supraspinal circuitry that contributes to descending modulation of excitability of spinal nociceptive neurons. We therefore determined whether ablation of spinal neurons that possess the NK-1 receptor altered descending systems that travel via the dorsolateral funiculus (DLF). Spontaneous activity and responses of dorsal horn neurons evoked by mechanical (von Frey monofilaments) and heat (35–51°C) stimuli were determined before and after transection of the DLF and were compared in rats pretreated with intrathecal application of vehicle or SP-SAP. In vehicle-treated rats, transection of the DLF caused a 233% increase in mean spontaneous activity of neurons and enhanced their responses to mechanical and heat stimuli, whereas these increases in excitation were blocked in rats pretreated with SP-SAP. Importantly, SP-SAP alone had no effect on spontaneous or evoked activity in the absence of DLF transection. These results demonstrate that spinal neurons expressing the NK-1 receptor appear to play a pivotal role in regulating descending systems that modulate activity of nociceptive dorsal horn neurons.

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