N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists block the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat's knee joint

1993 ◽  
Vol 70 (4) ◽  
pp. 1365-1377 ◽  
Author(s):  
V. Neugebauer ◽  
T. Lucke ◽  
H. G. Schaible

1. In 22 anesthetized rats we studied the involvement of N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the generation and maintenance of hyperexcitability in spinal cord neurons with knee input that develops in the course of an acute inflammation in the knee. In all experiments one neuron with knee input was identified, and the responses to mechanical stimuli and the receptive fields were monitored before and after induction of inflammation by the intra-articular injections of kaolin and carrageenan into the joint cavity. In most experiments multibarrel electrodes were used to administer specific NMDA and non-NMDA antagonists ionophoretically close to the neuron to test their effects on the inflammation-evoked changes. 2. Six neurons in the deep dorsal horn in six rats were used to establish the time course of the development of hyperexcitability in the untreated animal. In control periods of up to 3 h, the responses to mechanical stimuli and the receptive fields were stable. After induction of inflammation, the neurons developed increased responsiveness to mechanical stimuli applied to the injected knee but also to mechanical stimuli applied to the ipsilateral ankle and paw (including a reduction in the mechanical threshold in nociceptive specific neurons). The receptive fields expanded in five out of six neurons. The changes of responsiveness occurred mainly in the 2nd to 3rd h after the injection of kaolin. 3. In four rats three to four intravenous injections of the NMDA antagonist ketamine (2 mg/kg) were given during the injections of kaolin and carrageenan and in the following periods (up to 101 min postkaolin). During this treatment none of the four neurons exhibited the changes of responsiveness that were usually seen in control animals, although swelling of the knee developed in the same fashion as in control rats. Similarly, the generation of hyperexcitability was prevented when the NMDA antagonists ketamine and DL-2-amino-5-phosphonovalerate (AP5) were administered ionophoretically (ketamine in 4, AP5 in 2 rats) during the injections of kaolin and carrageenan and up to 100 min postkaolin. The doses of ketamine and AP5 were sufficient to reduce the responses to NMDA, whereas the responses to the non-NMDA agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were not influenced. 4. The ionophoretic application of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) during the injections of the kaolin and carrageenan and up to 103 min postkaolin also prevented the generation of hyperexcitability in six neurons in six rats.(ABSTRACT TRUNCATED AT 400 WORDS)

1989 ◽  
Vol 62 (4) ◽  
pp. 854-863 ◽  
Author(s):  
J. M. Laird ◽  
F. Cervero

1. Single-unit electrical activity has been recorded from 42 dorsal horn neurons in the sacral segments of the rat's spinal cord. The sample consisted of 20 multireceptive (class 2) cells with both A- and C-fiber inputs and 22 nocireceptive (class 3) cells. All neurons had cutaneous receptive fields (RFs) on the tail. 2. The RF sizes of the cells and their response thresholds to mechanical stimulation of the skin were determined before and after each of a series of 2-min noxious mechanical stimuli. Up to five such stimuli were delivered at intervals ranging from 10 to 60 min. In most cases, only one cell per animal was tested. 3. The majority of neurons were tested in barbiturate-anesthetized animals. However, to test whether or not this anesthetic influenced the results obtained, experiments were also performed in halothane-anesthetized and decerebrate-spinal preparations. The results from these experiments are considered separately. 4. All of the neurons responded vigorously to the first noxious pinch stimulus and all but one to the rest of the stimuli in the series. The responses of the neurons varied from stimulus to stimulus, but there were no detectable trends in the two groups of cells. 5. The RFs of the class 2 cells showed large increases (624.3 +/- 175.8 mm2, mean +/- SE) after the application of the pinch stimuli. The RFs of the class 3 neurons, which were initially smaller than those of the class 2 cells, either did not increase in size or showed very small increases after the pinch stimuli (38.3 +/- 11.95 mm2, mean +/- SE). 6. Some cells in both groups (6/10 class 2 cells and 7/16 class 3 cells) showed a decrease in mechanical threshold as a result of the noxious mechanical stimulus, but none of the class 3 cells' thresholds dropped below 20 mN into the low-threshold range. 7. The results obtained in the halothane-anesthetized and decerebrate-spinal animals were very similar to those seen in the barbiturate-anesthetized experiments, with the exception that in the decerebrate-spinal animals, the RFs of the class 2 cells were initially larger and showed only small increases.(ABSTRACT TRUNCATED AT 400 WORDS)


1995 ◽  
Vol 73 (4) ◽  
pp. 1574-1583 ◽  
Author(s):  
V. Neugebauer ◽  
F. Weiretter ◽  
H. G. Schaible

1. In anesthetized rats we studied the involvement of substance P and neurokinin-1 receptors in the generation and maintenance of hyperexcitability in spinal cord neurons, which develops in the course of an acute experimental inflammation in the knee. In all experiments one nociceptive neuron with knee input was identified, and the responses to mechanical stimuli and the receptive fields were monitored before and after induction of inflammation by the injections of kaolin and carrageenan into the knee joint. In 18 experiments either the specific antagonist at the neurokinin-1 receptor ionophoretically close to the neuron or intravenously during the injections of kaolin and carrageenan and in three periods of 15 min in the 95 min postkaolin (initial period of inflammation) to test their effects on the development of hyperexcitability. CP96,345 and CP96,344 were also administered after full development of inflammation to study their effects in hyperexcitable neurons. CP96,345 was ejected at currents that reduced or completely suppressed the effects of ionophoretically administered substance P but not those of neurokinin A, the agonist at neurokinin-2 receptors. 2. After the injections of kaolin and carrageenan into the knee joint, untreated control neurons (n = 8) developed hyperexcitability consisting of enhanced responses to noxious stimuli applied to the injected knee and the noninjected ankle, of an enhancement or induction of the responses to innocuous pressure applied to the joints and of an expansion of the receptive field. In eight neurons treated with ionophoretic administration of CP96,345 during the induction and initial period of inflammation, the development of hyperexcitability was not completely prevented but significantly attenuated. In comparison with the changes in the control neurons, the development of hyperexcitability was markedly reduced from the 2nd h up to 5 h postkaolin, but it was barely affected by CP96,345 within the 1st h postkaolin. Intravenous administration of CP96,345 in the initial period of inflammation produced a similar reduction of the development of hyperexcitability in another four neurons. The ionophoretic application of CP96,344 during and after induction of inflammation did not apparently impair the development of hyperexcitability (n = 6 neurons). 3. After development of inflammation and hyperexcitability, both the responses to innocuous and noxious pressure applied to the inflamed knee joint were reduced by the ionophoretic (n = 16 neurons) and intravenous administration (n = 9 neurons) of CP96,345 (tested 4.5-8 h postkaolin). Similarly, the responses to innocuous and noxious pressure applied to the noninflamed ankle were reduced by CP96,345 after inflammation had developed in the knee joint.(ABSTRACT TRUNCATED AT 400 WORDS)


2021 ◽  
Author(s):  
Line S Loken ◽  
Helena Backlund Wasling ◽  
Hakan Olausson ◽  
Francis S McGlone ◽  
Johan Wessberg

Numerous microneurography studies in the human peroneal nerve have suggested that CT afferents are lacking in the more distal parts of the limbs. Here we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves, with the most distal receptive fields located on the proximal phalanx of the third finger for the superficial branch of the radial nerve, and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial, radial and peroneal nerves. Moreover, we found that while CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared to C nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, including a lack of responsiveness to heat, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.


1977 ◽  
Vol 197 (1127) ◽  
pp. 169-194 ◽  

In rats anaesthetized with urethane, extracellular unit activity has been recorded from neurones in the central nervous system during noxious stimulation of the tail. Accurately graded and sustained stimulation was achieved by immersing the whole tail in water at controlled temperatures. Neurones were found chiefly in the marginal layers of the dorsal horn near the entry of the dorsal roots supplying the tail and in the ventrobasal nucleus of the thalamus; a few neurones were also found in the somatosensory cortex. Both dorsal horn units and thalamic units showed very similar responses as the tail temperature was gradually raised. At 42°C there was an increase in firing rate which rose sharply with increasing temperatures to reach a maximum at 46°C. At higher temperatures activ­ity declined and at temperatures above 50°C was largely extinguished. The temperature-response curves were bell-shaped. The decline in activity depended on temperature and not on time: sustained firing for many minutes was seen when temperature was at or just below the peak of the bell-shaped curve. The dorsal horn and thalamic cells also responded to noxious mechanical stimulation of the tail. The receptive fields at both levels were similar, being variable in size, often bilateral and sometimes covering the whole tail. None of the central neurones showed any response to noxious stimulation other than on the tail; neither did they respond to movement of the tail nor to light mechanical stimuli applied to the tail or elsewhere. In behavioural experiments conscious rats had their tails exposed to water at various temperatures. The rats lifted their tails from the water at a threshold temperature of 43.7 ± 0.6°C, i. e. just above the threshold for the central nociceptive neurones. The findings are compatible with a specific nociceptive pathway ascending to the ventrobasal thalamus.


1993 ◽  
Vol 69 (5) ◽  
pp. 1530-1540 ◽  
Author(s):  
K. Ren ◽  
M. Zhuo ◽  
A. Randich ◽  
G. F. Gebhart

1. The effects of electrical stimulation of cervical vagal afferent fibers on the nociceptive tail-flick (TF) reflex and responses of spinal dorsal horn neurons to noxious cutaneous stimulation were studied in adult rats treated as neonates with either capsaicin or vehicle. 2. Vagal afferent stimulation (VAS) produced biphasic, intensity-dependent effects on the TF reflex in vehicle-treated and untreated control rats. The TF reflex was facilitated in both groups of rats at lesser intensities of VAS (2.5-50 microA) and fully inhibited at greater intensities of VAS (50-100 microA). In contrast, biphasic effects of VAS on the TF reflex generally were not produced in rats treated as neonates with capsaicin. Facilitation of the TF reflex was produced in these rats by lesser intensities of VAS as well as by typically "inhibitory" intensities of VAS; the TF reflex was never inhibited in 6/12 rats, even at the greatest intensity of VAS tested (1,000 microA). When the TF reflex was inhibited by VAS in capsaicin-treated rats, the intensities required were significantly greater than those required in vehicle-treated or untreated rats. 3. In electrophysiological experiments, 77 neurons were recorded in the lumbar spinal dorsal horn of pentobarbital sodium-anesthetized, paralyzed rats treated as neonates with either vehicle or capsaicin. The neurons had receptive fields on the glabrous skin of the plantar surface of the ipsilateral hind foot, and all responded to mechanical stimuli of both nonnoxious and noxious intensities; 16/77 neurons also responded to noxious thermal stimulation. In vehicle-treated rats, nociceptive responses of 50% of 30 units studied were biphasically modulated by VAS, 33% were only inhibited, and 17% were only facilitated by VAS at the intensities tested (5-500 microA). In capsaicin-treated rats, nociceptive responses of 32% of 47 units studied were biphasically modulated by VAS, 15% were only inhibited, and 34% were only facilitated by VAS at the intensities tested (5-500 microA). In addition, nociceptive responses of neurons facilitated at lesser intensities of VAS and not affected at greater intensities of VAS were observed in capsaicin-treated rats (19% of the 47-unit sample). Overall, the proportion of the neuronal sample inhibited by VAS was less, and the proportion of the sample facilitated by VAS was greater in capsaicin-treated rats compared with vehicle-treated rats. 4. The efficacy of the capsaicin treatment was evaluated immunocytochemically.(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.


2012 ◽  
Vol 107 (1) ◽  
pp. 357-363 ◽  
Author(s):  
C. Ma ◽  
H. Nie ◽  
Q. Gu ◽  
P. Sikand ◽  
R. H. LaMotte

Native cowhage spicules, and heat-inactivated spicules containing histamine or capsaicin, evoke similar sensations of itch and nociceptive sensations in humans. In ongoing studies of the peripheral neural mechanisms of chemical itch and pain in the mouse, extracellular electrophysiological recordings were obtained, in vivo, from the cell bodies of mechanosensitive nociceptive neurons in response to spicule stimuli delivered to their cutaneous receptive fields (RFs) on the distal hindlimb. A total of 43 mechanosensitive, cutaneous, nociceptive neurons with axonal conduction velocities in the C-fiber range (C-nociceptors) were classified as CM if responsive to noxious mechanical stimuli, such as pinch, or CMH if responsive to noxious mechanical and heat stimuli (51°C, 5 s). The tips of native cowhage spicules, or heat-inactivated spicules containing histamine or capsaicin, were applied to the RF. Heat-inactivated spicules containing no chemical produced only a transient response occurring during insertion. Of the 43 mechanosensitive nociceptors recorded, 20 of the 25 CMHs responded to capsaicin, and of these, 13 also responded to cowhage and/or histamine. In contrast, none of the 18 CMs responded to any of the chemical stimuli. The time course of the mean discharge rate of CMHs was similar in response to each type of spicule and generally similar, although reaching a peak earlier, to the temporal profiles of itch and nociceptive sensations evoked by the same stimuli in humans. These findings are consistent with the hypothesis that the itch and nociceptive sensations evoked by these punctuate chemical stimuli are mediated at least in part by the activity of mechanoheat-sensitive C-nociceptors. In contrast, activity in mechanosensitive C-nociceptors that do not respond to heat or to pruritic chemicals is hypothesized as contributing to pain but not to itch.


1980 ◽  
Vol 44 (5) ◽  
pp. 862-877 ◽  
Author(s):  
D. Menetrey ◽  
A. Chaouch ◽  
J. M. Besson

1. Spinoreticular tract neurons at the rat lumbar cord level were identified by antidromic activation following stimulation at mainly pontine and mesencephalic levels. These units, which were found in the dorsal half of the cord, could be separated into two groups according to their spinal location, electrophysiological properties, and their central projections. 2. Units in the dorsolateral funiculus nucleus projected mainly to the cuneiformis area and adjacent structures with frequent bilateral projections. They had the slowest conduction velocities, sometimes in the unmyelinated range. Generally, they were driven only by stimulation of subcutaneous and/or deep structures. 3. Neurons located in the dorsal horn mainly projected contralaterally to pontine and mesencephalic levels. their conduction velocities and the electrophysiological properties were identical to those observed for the rat spinothalamic tract (22). Almost all (86%) had clear cutaneous sensitivity and generally large receptive fields: 40% responded to nonnoxious and noxious mechanical cutaneous stimuli and frequently to noxious radiant heat, 26% were exclusively excited by light tactile stimuli, and 20% required noxious cutaneous mechanical stimulation for activation. There was a good correlation between responses to natural and transcutaneous electrical stimulation: units driven by noxious mechanical stimuli received A-delta- and/or C-fiber inputs. The remaining units (14%) had more complex receptive fields associated with both excitatory and inhibitory inputs originating from a single peripheral area. 4. The functional heterogeneity of the rat spinoreticular tract is reminiscent of that demonstrated for the rat and monkey spinothalamic tracts. Similarly, the rat spinoreticular neurons are under the influence of descending inhibitory controls originating from the nucleus raphe magnus and bulbar reticular formation. 5. Responses of the rat spinoreticular tract neurons are consistent with the involvement of this pathway in the transmission of messages of both innocuous and noxious origins.


Author(s):  
Line Sofie Loken ◽  
Helena Backlund Wasling ◽  
Håkan Olausson ◽  
Francis McGlone ◽  
Johan Wessberg

Unmyelinated tactile (CT) afferents are abundant in arm hairy skin and have been suggested to signal features of social affective touch. Here we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves, with the most distal receptive fields located on the proximal phalanx of the third finger for the superficial branch of the radial nerve, and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial (n=27), radial (n=8) and peroneal nerves (n=4). Moreover, we found that while CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared to C nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.


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)


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