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

2015 ◽  
Vol 114 (4) ◽  
pp. 2528-2534 ◽  
Author(s):  
T. Akiyama ◽  
M. Nagamine ◽  
A. Davoodi ◽  
M. Iodi Carstens ◽  
F. Cevikbas ◽  
...  

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.

2000 ◽  
Vol 84 (2) ◽  
pp. 616-627 ◽  
Author(s):  
Steven L. Jinks ◽  
E. Carstens

We have investigated whether neurons in superficial laminae of the spinal dorsal horn respond to intracutaneous (ic) delivery of histamine and other irritant chemicals, and thus might be involved in signaling sensations of itch or chemogenic pain. Single-unit recordings were made from superficial lumbar dorsal horn neurons in pentobarbital sodium–anesthetized rats. Chemoresponsive units were identified using ic microinjection of histamine (3%, 1 μl) into the hindpaw as a search stimulus. All superficial units so identified [9 nociceptive-specific (NS), 26 wide-dynamic-range (WDR)] responded to subsequent ic histamine. A comparison group of histamine-responsive deep dorsal horn neurons ( n = 16) was similarly identified. The mean histamine-evoked discharge decayed to 50% of the maximal rate significantly more slowly for the superficial (92.2 s ± 65.5, mean ± SD) compared with deep dorsal horn neurons (28.2 s ± 11.6). In addition to responding to histamine, most superficial dorsal horn neurons were also excited by ic nicotine (22/25 units), capsaicin (21/22), topical mustard oil (5/6), noxious heat (26/30), and noxious and/or innocuous mechanical stimuli (except for 1 unit that did not have a mechanosensitive receptive field). Application of a brief noxious heat stimulus during the response to ic histamine evoked an additive response in all but two cases, followed by transient depression of firing in 11/20 units. Intrathecal (IT) administration of morphine had mixed effects on superficial dorsal horn neuronal responses to ic histamine and noxious heat. Low morphine concentrations (100 nM to 1 μM) facilitated histamine-evoked responses (to >130% of control) in 9/24 units, depressed the responses (by >70%) in 11/24, and had no effect in 4. Naloxone reversed morphine-induced effects in some but not all cases. A higher morphine concentration (10 μM) had a largely depressant, naloxone-reversible effect on histamine responses. Responses of the same superficial neurons to noxious heat were facilitated (15/25), reduced (8/25), or unaffected (2/25) by low morphine concentrations and were depressed by the higher morphine concentration. In contrast, deep dorsal horn neuronal responses to both histamine and noxious heat were primarily depressed by low concentrations of morphine in a naloxone-reversible manner. These results indicate that superficial dorsal horn neurons respond to both pruritic and algesic chemical stimuli and thus might participate in transmitting sensations of itch and/or chemogenic pain. The facilitation of superficial neuronal responses to histamine by low concentrations of morphine, coupled with inhibition of deep dorsal horn neurons, might underlie the development of pruritis that is often observed after epidural morphine.


2003 ◽  
Vol 90 (1) ◽  
pp. 73-80 ◽  
Author(s):  
Yuan Bo Peng ◽  
Qing Dong Ling ◽  
M. A. Ruda ◽  
Daniel R. Kenshalo

Neonatal peripheral inflammation has been shown to produce profound anatomical changes in the dorsal horn of adult rats. In this study, we explored whether parallel physiological changes exist. Neonatal rats were injected with complete Freund's adjuvant (CFA) into the left hind paw. At 8–10 wk of age, single dorsal horn neurons were recorded in response to graded intensities of mechanical stimuli delivered to the receptive field. In addition, cord dorsum potentials, produced by electrical stimuli delivered to the left sciatic nerve at 2.5× threshold, were recorded bilaterally from L2 to S3. There were significant increases in background activity and responses to brush and pinch in neonatal rats that were treated with CFA, as compared with control rats. Further analysis showed similar significant changes when dorsal horn neurons were categorized into wide dynamic range (WDR), high-threshold (HT), and low-threshold (LT) groups. The receptive field was significantly larger in neonatally treated rats as compared with control rats. Additionally, there was a significant increase in the response to a 49°C heat stimulus in neonatally treated rats as compared with control rats. There was also a trend for the amplitudes of N1, N2, and P waves of the cord dorsum potential to increase and latencies to decrease in neonatally treated rats, but no significant differences were detected between different levels of the spinal cord (L2 to S3). These data further support the notion that anatomical and physiological plasticity changes occurred in the spinal cord following early neonatal CFA treatment.


1989 ◽  
Vol 62 (2) ◽  
pp. 437-449 ◽  
Author(s):  
W. Maixner ◽  
R. Dubner ◽  
D. R. Kenshalo ◽  
M. C. Bushnell ◽  
J. L. Oliveras

1. We examined the activity of thermally sensitive trigeminothalamic neurons and nonprojection neurons in the medullary dorsal horn (trigeminal nucleus caudalis) in three monkeys performing thermal and visual detection tasks. 2. An examination of neuronal stimulus-response functions, obtained during thermal-detection tasks in which noxious heat stimuli were applied to the face, indicated that wide-dynamic-range neurons (WDR, responsive to innocuous mechanical stimuli with greater responses to noxious mechanical stimuli) could be subclassified based on the slope values of linear regression lines. WDR1 neurons exhibited significantly greater sensitivity to noxious heat stimulation than WDR2 neurons or nociceptive-specific neurons (NS, responsive only to noxious stimuli). 3. In one behavioral task, the monkeys detected 1.0 degrees C increases in noxious heat from preceding noxious heat stimuli ranging from 44 to 48 degrees C. WDR1, WDR2, and NS neurons increased their discharge frequency as a function of the intensity of the first noxious heat temperature (T1) as well as the final temperature (T2). The responses of WDR1 neurons were greater than those produced by WDR2 or NS neurons across all the temperatures examined. The order of stimulus presentation affected the responses of WDR1 neurons to 1.0 degrees C increases in the noxious heat range but not those of WDR2 or NS neurons. 4. In a second behavioral task, the monkeys detected small increases in noxious heat (0.2-0.8 degrees C) from a first temperature of 46 degrees C. Although the responses of all three classes of neurons were monotonically related to stimulus intensity, WDR1 neurons exhibited greater sensitivity to small temperature increases than either WDR2 or NS neurons. 5. Subpopulations of all three classes of neurons exhibited responses that were independent of thermal stimulus parameters or sensory modality and that only occurred during the behavioral task. These task-related responses were time-locked to specific behavioral events associated with trial initiation and trial continuation. 6. These data provide evidence that a subpopulation of WDR neurons is the dorsal horn cell type most sensitive to small increases in noxious heat in the 45-49 degrees C temperature range and provides the most information about stimulus intensity. The findings support the view that nociceptive neurons have the capacity to precisely encode stimulus features in the noxious range and that WDR neurons are likely to participate in the monkeys' ability to perceive the intensity of such stimuli.


2009 ◽  
Vol 102 (4) ◽  
pp. 2176-2183 ◽  
Author(s):  
Tasuku Akiyama ◽  
Mirela Iodi Carstens ◽  
E. Carstens

Recent studies have suggested the existence of separate transduction mechanisms and sensory pathways for histamine and nonhistaminergic types of itch. We studied whether histamine and an agonist of the protease-activated receptor (PAR)-2, associated with nonhistaminergic itch, excite murine dorsal horn neurons. Single units were recorded in superficial lumbar dorsal horn of adult ICR mice anesthetized with pentobarbital. Unit activity was searched using a small intradermal hindpaw injection of histamine or the PAR-2 agonist SLIGRL-NH2. Isolated units were subsequently challenged with intradermal histamine followed by SLIGRL-NH2 (each 50 μg/1 μl) or reverse order, followed by mechanical, thermal, and algogenic stimuli. Forty-three units were classified as wide dynamic range (62%), nociceptive specific (22%), or mechano insensitive (16%). Twenty units gave prolonged (mean, 10 min) discharges to intradermal injection of histamine; 76% responded to subsequent SLIGRL-NH2, often more briefly. Units additionally responded to noxious heat (63%), cooling (43%), topical mustard oil (53%), and intradermal capsaicin (67%). Twenty-two other units gave prolonged (mean, 5 min) responses to initial intradermal injection of SLIGRL-NH2; 85% responded to subsequent intradermal histamine. They also responded to noxious heat (75%), mustard oil (93%), capsaicin (63%), and one to cooling. Most superficial dorsal horn neurons were excited by both histamine and the PAR-2 agonist, suggesting overlapping pathways for histamine- and non–histamine-mediated itch. Because the large majority of pruritogen-responsive neurons also responded to noxious stimuli, itch may be signaled at least partly by a population code.


1996 ◽  
Vol 75 (6) ◽  
pp. 2606-2628 ◽  
Author(s):  
J. T. Katter ◽  
R. J. Dado ◽  
E. Kostarczyk ◽  
G. J. Giesler

1. A goal of this study was to determine whether neurons in the sacral spinal cord that project to the diencephalon are involved in the processing and transmission of sensory information that arises in the perineum and pelvis. Therefore, 58 neurons in segments L6-S2 were activated antidromically with currents < or = 30 microA from points in the contralateral diencephalon in rats that were anesthetized with urethan. 2. Responses to mechanical stimuli applied to the cutaneous receptive fields of these neurons were used to classify them as low-threshold (LT), wide dynamic range (WDR) or high-threshold (HT) neurons. Twenty-two neurons (38%) responded preferentially to brushing (LT neurons). Eighteen neurons (31%) responded to brushing but responded with higher firing frequencies to noxious mechanical stimuli (WDR neurons). Eighteen neurons (31%) responded only to noxious intensities of mechanical stimulation (HT neurons). LT neurons were recorded predominantly in nucleus proprius of the dorsal horn. Nociceptive neurons (WDR and HT) were recorded throughout the dorsal horn. 3. Cutaneous receptive fields were mapped for 56 neurons. Forty-five (80%) had receptive fields that included at least two of the following regions ipsilaterally: the rump, perineum, or tail. Eleven neurons (20%) had receptive fields that were restricted to one of these areas or to the ipsilateral hind limb. Thirty-eight neurons (68%) had cutaneous receptive fields that also included regions of the contralateral tail or perineum. On the perineum, receptive fields usually encompassed perianal and perivaginal areas including the clitoral sheath. There were no statistically significant differences in the locations or sizes of receptive fields for LT neurons compared with nociceptive (WDR and HT) neurons. 4. Thirty-seven LT, WDR, and HT neurons were tested for their responsiveness to heat stimuli. Five (14%) responded to increasing intensities of heat with graded increases in their firing frequencies. Thirty-two LT, WDR, and HT neurons also were tested with cold stimuli. None responded with graded increases in their firing frequencies to increasingly colder stimuli. There were no statistically significant differences among the responses of LT, WDR, and HT neurons to either heat or cold stimuli. 5. Forty LT, WDR, and HT neurons were tested for their responsiveness to visceral stimuli by distending a balloon placed into the rectum and colon with a series of increasing pressures. Seventeen (43%) exhibited graded increases in their firing frequencies in response to increasing pressures of colorectal distention (CrD). None of the responsive neurons responded reproducibly to CrD at an intensity of 20 mmHg, and all responded at intensities of > or = 80 mmHg. More than 90% responded abruptly at stimulus onset, responded continuously throughout the stimulus period, and stopped responding immediately after termination of the stimulus. 6. Thirty-one neurons were tested for their responsiveness to distention of a balloon placed inside the vagina. Eleven (35%) exhibited graded increases in their firing frequencies in response to increasing pressures of vaginal distention (VaD). The thresholds and temporal profiles of the responses to VaD were similar to those for CrD. Twenty-nine neurons were tested with both CrD and VaD. Thirteen (45%) were excited by both stimuli, four (14%) responded to CrD but not VaD, and one (3%) was excited by VaD but not CrD. Neurons excited by CrD, VaD, or both were recorded throughout the dorsal horn. 7. As a population, WDR neurons, but not LT or HT neurons, encoded increasing pressures of CrD and VaD with graded increases in their firing frequencies. The responses of WDR neurons to CrD differed significantly from those of either LT or HT neurons. Regression analyses of the stimulus-response functions of responsive WDR neurons to CrD and VaD were described by power functions with exponents of 1.6 and 2.4, respectively.(ABSTRACT TRUNCATED)


1994 ◽  
Vol 72 (2) ◽  
pp. 612-621 ◽  
Author(s):  
S. P. Schneider ◽  
E. R. Perl

1. Responses of dorsal horn neurons to cutaneous mechanical stimulation were studied in an in vitro preparation of hamster spinal cord with partially intact innervation from an isolated patch of hairy skin. Stable extracellular and intracellular recordings were obtained from cells with different mechanoreceptive properties similar to those reported for other species in vivo. Analyses were made of the intracellular responses of 25 dorsal horn neurons activated selectively by mechanical stimulation to the skin patch. 2. Bath application of the broad spectrum, excitatory amino acid (EAA) receptor antagonist, kynurenic acid (1 mM) blocked excitation of 7 of 8 high-threshold mechanoreceptive units by either cutaneous nerve volleys or mechanical stimulation of the skin. This concentration of kynurenic acid suppressed peripherally evoked responses in 8 of 14 neurons responsive to innocuous mechanical stimuli. 3. High-threshold mechanoreceptive neurons of the superficial dorsal horn exhibited one of three distinctive patterns of postsynaptic potentials in response to electrical stimulation of cutaneous afferent fibers: 1) a simple fast excitatory postsynaptic potential (EPSP), 2) a fast EPSP with a prolonged decay phase lasting between 100 and 1,000 ms, and 3) a multiphasic response dissociable on the basis of stimulus strength consisting of a fast EPSP followed by a hyperpolarizing inhibitory postsynaptic potential (IPSP) (duration 80–100 ms). Gentle mechanical stimuli initiated inhibition from areas adjacent to the high-threshold mechanically excitatory field; this suggests that membrane hyperpolarization in these neurons was evoked by input from low-threshold mechanoreceptors. 4. Bath application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), a competitive EAA antagonist selective for non-N-methyl-D-aspartate (non-NMDA) receptor subtypes, substantially or completely (56–100%) suppressed EPSPs evoked from cutaneous afferent fibers in high-threshold mechanoreceptive neurons. CNQX also decreased the membrane depolarization, the frequency of EPSPs, and the frequency of action potentials evoked by mechanical stimulation of the receptive field. 5. CNQX (10 microM) or kynurenic acid (1 mM) had considerably weaker effects on IPSPs than on EPSPs evoked from the periphery in superficial dorsal horn neurons. IPSP amplitudes were unchanged by these agents in some neurons and decreased by only 20–25% in others. 6. We conclude that L-glutamate acting on non-NMDA receptors mediates fast synaptic excitation of superficial dorsal horn neurons from peripheral mechanical nociceptors with myelinated fibers. Furthermore, the observations imply either an agent other than L-glutamate or one acting at different membrane receptors is a synaptic mediator for other peripheral afferent units including some activated by innocuous mechanical stimuli.


1998 ◽  
Vol 80 (4) ◽  
pp. 2210-2214 ◽  
Author(s):  
Kai-Ming Zhang ◽  
Xiao-Min Wang ◽  
Angela M. Peterson ◽  
Wen-Yan Chen ◽  
Sukhbir S. Mokha

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.


1989 ◽  
Vol 62 (2) ◽  
pp. 450-457 ◽  
Author(s):  
R. Dubner ◽  
D. R. Kenshalo ◽  
W. Maixner ◽  
M. C. Bushnell ◽  
J. L. Oliveras

1. We examined the relationship between the activity of medullary dorsal horn nociceptive neurons and the monkeys' ability to detect noxious heat stimuli. In two different detection tasks, the temperature of a contact thermode positioned on the monkey's face increased from 38 degrees C to temperatures between 44 and 48 degrees C (T1). After a variable time period, the thermode temperature increased an additional 0.2-1.5 degrees C (T2), and the monkeys' detection speed from the onset of T2 was determined. We previously have established that detection speed is a measure of the perceived intensity of noxious thermal stimuli. Nociceptive neurons were classified as wide-dynamic-range (WDR, responsive to innocuous mechanical stimuli with greater responses to noxious mechanical stimuli) and nociceptive-specific (NS, responsive only to noxious stimuli). WDR neurons were subclassified as WDR1 and WDR2 based on the higher slope values of the stimulus-response functions of WDR1 neurons. The monkeys were trained to detect small increases in noxious heat, and their detection speeds were correlated with the responses of WDR1, WDR2, and NS neurons. 2. Detection speeds to T2 temperatures of 1.0 degrees C from preceding T1 temperatures of 45 and 46 degrees C were faster during a preceding ascending series of stimuli than during a descending series. Similarly, the peak discharge frequencies of WDR1 neurons in response to the same stimuli were greater during the ascending series of T2 temperatures. In contrast, the responses of WDR2 and NS neurons showed no significant differences during the ascending and descending series of stimuli. 3. Detection speeds following 0.4, 0.6, and 0.8 degrees C T2 stimuli were higher when the preceding T1 temperature was 46 degrees C as compared with detection speeds to the identical stimuli when the preceding T1 temperature was 45 degrees C. WDR1 neurons also exhibited a significant increase in peak discharge frequency to these same T2 stimuli when the preceding T1 temperature was 46 degrees C. In contrast, the neuronal activity of WDR2 and NS neurons did not differ on 45 and 46 degrees C T1 trials. 4. The relationship between detection speed and neuronal peak discharge frequency was examined in response to different pairs of T1 and T2 stimuli when T1 was either 45 or 46 degrees C. There was a significant correlation between detection speed and neuronal discharge for WDR1 and WDR2 neurons. No correlation was observed for NS neurons. 5. The magnitude of neuronal activity on correctly detected and nondetected trials was compared when T1 was 46 degrees C and T2 was 0.2 degree C.(ABSTRACT TRUNCATED AT 400 WORDS)


1994 ◽  
Vol 71 (3) ◽  
pp. 959-980 ◽  
Author(s):  
R. J. Dado ◽  
J. T. Katter ◽  
G. J. Giesler

1. Seventy-seven neurons in the cervical enlargement of rats anesthetized with urethan were initially antidromically activated using currents < or = 30 microA from the contralateral posterior thalamus. A goal of these experiments was to determine the course of physiologically characterized spinal axons within the diencephalon. Therefore, in 38 cases, additional antidromic mapping was done throughout the mediolateral extent of the diencephalon at multiple anterior-posterior planes. 2. Electrolytic lesions marking the recording sites were recovered for 71 neurons. Thirty-one were located in the superficial dorsal horn (SDH); 39 were in nucleus proprius or the lateral reticulated area of the deep dorsal horn (DDH), and one was in the ventral horn. 3. Eight of 38 (21%) neurons that were tested for more anterior projections could only be antidromically activated with currents < or = 30 microA from sites in the contralateral posterior thalamus. Such neurons are referred to as spinothalamic tract (STT) neurons. Lesions marking the lowest threshold points for antidromic activation were located in or near the posterior thalamic group (Po). At more anterior levels, considerably higher currents were required for antidromic activation or it was not possible to activate the neurons with currents up to 500 microA. Four of these neurons were physiologically characterized and each responded preferentially to noxious mechanical stimuli (wide dynamic range, WDR). Each of the three neurons that were tested responded to noxious heat stimuli. These findings confirm anatomic studies that have shown that a number of STT axons terminate in Po and suggest that such axons that originate in the cervical enlargement carry nociceptive input from the upper extremity. 4. In 15 cases, electrode penetrations were made systematically throughout much of the contralateral ventrobasal complex (VbC). In 17 cases, penetrations were made throughout the intralaminar nuclei contralaterally, including the central lateral nucleus (CL). Surprisingly, only one of the examined axons was antidromically activated with low currents from CL and one from VbC, although both of these nuclei are known to receive sizeable inputs from the STT. 5. Many of the axons (27 of the 38 tested, 71%) that were initially antidromically activated from the contralateral posterior thalamus could also be antidromically activated with low currents (< or = 30 microA) and at increased latencies from sites located anteriorly in the contralateral hypothalamus. Such neurons are referred to as spinothalamic tract/spinohypothalamic tract (STT/SHT) neurons.(ABSTRACT TRUNCATED AT 400 WORDS)


2001 ◽  
Vol 86 (2) ◽  
pp. 986-996 ◽  
Author(s):  
Sergey G. Khasabov ◽  
David M. Cain ◽  
Dinh Thong ◽  
Patrick W. Mantyh ◽  
Donald A. Simone

The effects of a mild freeze injury to the skin on responses of nociceptive dorsal horn neurons to cold and heat stimuli were examined in anesthetized rats. Electrophysiological recordings were obtained from 72 nociceptive spinal neurons located in the superficial and deep dorsal horn. All neurons had receptive fields (RFs) on the glabrous skin of the hindpaw, and neurons were functionally divided into wide dynamic range (WDR) and high-threshold (HT) neurons. Forty-four neurons (61%) were classified as WDR and responded to both innocuous and noxious mechanical stimuli (mean mechanical threshold of 12.8 ± 1.6 mN). Twenty-eight neurons (39%) were classified as HT and were excited only by noxious mechanical stimuli (mean mechanical threshold of 154.2 ± 18.3 mN). Neurons were characterized for their sensitivity heat (35 to 51°C) and cold (28 to −12°C) stimuli applied to their RF. Among WDR neurons, 86% were excited by both noxious heat and cold stimuli, while 14% responded only to heat. For HT neurons, 61% responded to heat and cold stimuli, 32% responded only to noxious heat, and 7% responded only to noxious cold. Effects of a mild freeze injury (−15°C applied to the RF for 20 s) on responses to heat and cold stimuli were examined in 30 WDR and 22 HT neurons. Skin freezing was verified as an abrupt increase in skin temperature at the site of injury due to the exothermic reaction associated with crystallization. Freezing produced a decrease in response thresholds to heat and cold stimuli in most WDR and HT neurons. WDR and HT neurons exhibited a mean decrease in response threshold for cold of 9.0 ± 1.3°C and 10.0 ± 1.6°C, respectively. Mean response thresholds for heat decreased 4.0 ± 0.4°C and 4.3 ± 1.3°C in WDR and HT neurons, respectively. In addition, responses to suprathreshold cold and heat stimuli increased. WDR and HT neurons exhibited an 89% and a 192% increase in response across all cold stimuli, and a 93 and 92% increase in responses evoked across all heat stimuli, respectively. Our results demonstrate that many spinal neurons encode intensity of noxious cold as well as noxious heat over a broad range of stimulus temperatures. Enhanced responses of WDR and HT neurons to cold and heat stimuli after a mild freeze injury is likely to contribute to thermal hyperalgesia following a similar freeze injury in humans.


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