scholarly journals Descending antinociception induced by secondary somatosensory cortex stimulation in experimental neuropathy: role of the medullospinal serotonergic pathway

2017 ◽  
Vol 117 (3) ◽  
pp. 1200-1214 ◽  
Author(s):  
Boriss Sagalajev ◽  
Hanna Viisanen ◽  
Hong Wei ◽  
Antti Pertovaara
Keyword(s):  
Somatosensory Cortex ◽  
Receptor Agonist ◽  
Dynamic Range ◽  
Antinociceptive Effect ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Secondary Somatosensory Cortex ◽  
Underlying Mechanisms ◽  
Wdr Neurons ◽  
Stimulation Of

Stimulation of the secondary somatosensory cortex (S2) has attenuated pain in humans and inflammatory nociception in animals. Here we studied S2 stimulation-induced antinociception and its underlying mechanisms in an experimental animal model of neuropathy induced by spinal nerve ligation (SNL). Effect of S2 stimulation on heat-evoked limb withdrawal latency was assessed in lightly anesthetized rats that were divided into three groups based on prior surgery and monofilament testing before induction of anesthesia: 1) sham-operated group and 2) hypersensitive and 3) nonhypersensitive (mechanically) SNL groups. In a group of hypersensitive SNL animals, a 5-HT1A receptor agonist was microinjected into the rostroventromedial medulla (RVM) to assess whether autoinhibition of serotonergic cell bodies blocks antinociception. Additionally, effect of S2 stimulation on pronociceptive ON-cells and antinociceptive OFF-cells in the RVM or nociceptive spinal wide dynamic range (WDR) neurons were assessed in anesthetized hypersensitive SNL animals. S2 stimulation induced antinociception in hypersensitive but not in nonhypersensitive SNL or sham-operated animals. Antinociception was prevented by a 5-HT1A receptor agonist in the RVM. Antinociception was associated with decreased duration of heat-evoked response in RVM ON-cells. In spinal WDR neurons, heat-evoked discharge was delayed by S2 stimulation, and this antinociceptive effect was prevented by blocking spinal 5-HT1A receptors. The results indicate that S2 stimulation suppresses nociception in SNL animals if SNL is associated with tactile allodynia-like hypersensitivity. In hypersensitive SNL animals, S2 stimulation induces antinociception mediated by medullospinal serotonergic pathways acting on the spinal 5-HT1A receptor, and partly through reduction of the RVM ON-cell discharge. NEW & NOTEWORTHY Stimulation of S2 cortex, but not that of an adjacent cortical area, induced descending heat antinociception in rats with the spinal nerve ligation-induced model of neuropathy. Antinociception was bilateral, and it involved suppression of pronociceptive medullary cells and activation of serotonergic pathways that act on the spinal 5-HT1A receptor. S2 stimulation failed to induce descending antinociceptive effect in sham-operated controls or in nerve-ligated animals that had not developed mechanical hypersensitivity.

Spinal GABAAand GABABReceptor Pharmacology in a Rat Model of Neuropathic Pain

2002 ◽  
Vol 96 (5) ◽  
pp. 1161-1167 ◽  
Author(s):  
T. Philip Malan ◽  
Heriberto P. Mata ◽  
Frank Porreca
Keyword(s):  
Neuropathic Pain ◽  
Receptor Antagonist ◽  
Motor Function ◽  
Receptor Agonist ◽  
Gabab Receptor ◽  
Thermal Hyperalgesia ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Tactile Allodynia ◽  
Withdrawal Latency

Background This study tests the hypothesis that loss of spinal activity of gamma-aminobutyric acid (GABA) contributes to the allodynia and hyperalgesia observed after peripheral nerve injury. Methods Intrathecal catheters were implanted in male Sprague-Dawley rats. Antinociception was assessed by measuring withdrawal latency to immersion of the tail in a 52 degrees C water bath. Nerve injury was produced by ligation of the L5 and L6 spinal nerves. Testing was performed 4-14 days after spinal nerve ligation, when tactile allodynia and thermal hyperalgesia were established. Tactile allodynia was quantitated using the threshold to withdrawal of the hind paw on probing with von Frey filaments. Thermal hyperalgesia was quantitated using the latency to withdrawal of the hind paw from radiant heat. Motor function was tested using a rotarod apparatus. Results Spinal administration of the GABAA receptor antagonist bicuculline or the GABAB receptor antagonist phaclofen produced tactile allodynia and thermal hyperalgesia in normal rats. The GABAB receptor agonist baclofen, administered spinally, produced antinociception in the tail-flick test, whereas the GABAA receptor agonist isoguvacine did not. Isoguvacine and baclofen each reversed tactile allodynia and thermal hyperalgesia produced by spinal nerve ligation. Baclofen but not isoguvacine prolonged thermal withdrawal latency in nerve-injured rats beyond preoperative values. Baclofen but not isoguvacine impaired motor function. Conclusions Pharmacologic inhibition of intrinsic GABA tone in normal rats resulted in tactile allodynia and thermal hyperalgesia, consistent with the hypothesis being tested. Exogenous administration of GABA agonists reversed spinal nerve ligation-induced allodynia and hyperalgesia, also consistent with this hypothesis. Isoguvacine produced specific antihyperalgesic and antiallodynic effects, whereas assessment of the effects of baclofen was complicated by motor dysfunction. Spinal GABAA agonists may provide a specific therapy for neuropathic pain.

Response Properties and Organization of Nociceptive Neurons in Area 1 of Monkey Primary Somatosensory Cortex

2000 ◽  
Vol 84 (2) ◽  
pp. 719-729 ◽  
Author(s):  
Dan R. Kenshalo ◽  
Koichi Iwata ◽  
Maurice Sholas ◽  
David A. Thomas
Keyword(s):  
Somatosensory Cortex ◽  
Dynamic Range ◽  
Receptive Fields ◽  
Primary Somatosensory Cortex ◽  
Isolated Cells ◽  
Nociceptive Neurons ◽  
Response Properties ◽  
Stimulus Response ◽  
Noxious Mechanical Stimulation ◽  
Wdr Neurons

The organization and response properties of nociceptive neurons in area 1 of the primary somatosensory cortex (SI) of anesthetized monkeys were examined. The receptive fields of nociceptive neurons were classified as either wide-dynamic-range (WDR) neurons that were preferentially responsive to noxious mechanical stimulation, or nociceptive specific (NS) that were responsive to only noxious stimuli. The cortical locations and the responses of the two classes of neurons were compared. An examination of the neuronal stimulus-response functions obtained during noxious thermal stimulation of the glabrous skin of the foot or the hand indicated that WDR neurons exhibited significantly greater sensitivity to noxious thermal stimuli than did NS neurons. The receptive fields of WDR neurons were significantly larger than the receptive fields of NS neurons. Nociceptive SI neurons were somatotopically organized. Nociceptive neurons with receptive fields on the foot were located more medial in area 1 of SI than those with receptive fields on the hand. In the foot representation, the recording sites of nociceptive neurons were near the boundary between areas 3b and 1, whereas in the hand area, there was a tendency for them to be located more caudal in area 1. The majority of nociceptive neurons were located in the middle layers (III and IV) of area 1. The fact that nociceptive neurons were not evenly distributed across the layers of area 1 suggested that columns of nociceptive neurons probably do not exist in the somatosensory cortex. In electrode tracks where nociceptive neurons were found, approximately half of all subsequently isolated neurons were also classified as nociceptive. Low-threshold mechanoreceptive (LTM) neurons were intermingled with nociceptive neurons. Both WDR and NS neurons were found in close proximity to one another. In instances where the receptive field shifted, subsequently isolated cells were also classified as nociceptive. These data suggest that nociceptive neurons in area 1 of SI are organized in vertically orientated aggregations or clusters in layers III and IV.

Trigeminohypothalamic and Reticulohypothalamic Tract Neurons in the Upper Cervical Spinal Cord and Caudal Medulla of the Rat

2000 ◽  
Vol 84 (4) ◽  
pp. 2078-2112 ◽  
Author(s):  
Amy Malick ◽  
Rew M. Strassman ◽  
Rami Burstein
Keyword(s):  
Spinal Cord ◽  
Trigeminal Nerve ◽  
Dynamic Range ◽  
Cervical Spinal Cord ◽  
Red Nucleus ◽  
Receptive Fields ◽  
Upper Cervical ◽  
Caudal Medulla ◽  
Wdr Neurons ◽  
Stimulation Of

Sensory information that arises in orofacial organs facilitates exploratory, ingestive, and defensive behaviors that are essential to overall fitness and survival. Because the hypothalamus plays an important role in the execution of these behaviors, sensory signals conveyed by the trigeminal nerve must be available to this brain structure. Recent anatomical studies have shown that a large number of neurons in the upper cervical spinal cord and caudal medulla project directly to the hypothalamus. The goal of the present study was to identify the types of information that these neurons carry to the hypothalamus and to map the route of their ascending axonal projections. Single-unit recording and antidromic microstimulation techniques were used to identify 81 hypothalamic-projecting neurons in the caudal medulla and upper cervical (C1) spinal cord that exhibited trigeminal receptive fields. Of the 72 neurons whose locations were identified, 54 were in laminae I–V of the dorsal horn at the level of C1 ( n = 22) or nucleus caudalis (Vc, n = 32) and were considered trigeminohypothalamic tract (THT) neurons because these regions are within the main projection territory of trigeminal primary afferent fibers. The remaining 18 neurons were in the adjacent lateral reticular formation (LRF) and were considered reticulohypothalamic tract (RHT) neurons. The receptive fields of THT neurons were restricted to the innervation territory of the trigeminal nerve and included the tongue and lips, cornea, intracranial dura, and vibrissae. Based on their responses to mechanical stimulation of cutaneous or intraoral receptive fields, the majority of THT neurons were classified as nociceptive (38% high-threshold, HT, 42% wide-dynamic-range, WDR), but in comparison to the spinohypothalamic tract (SHT), a relatively high percentage of low-threshold (LT) neurons were also found (20%). Responses to thermal stimuli were found more commonly in WDR than in HT neurons: 75% of HT and 93% of WDR neurons responded to heat, while 16% of HT and 54% of WDR neurons responded to cold. These neurons responded primarily to noxious intensities of thermal stimulation. In contrast, all LT neurons responded to innocuous and noxious intensities of both heat and cold stimuli, a phenomenon that has not been described for other populations of mechanoreceptive LT neurons at spinal or trigeminal levels. In contrast to THT neurons, RHT neurons exhibited large and complex receptive fields, which extended over both orofacial (“trigeminal”) and extracephalic (“non-trigeminal”) skin areas. Their responses to stimulation of trigeminal receptive fields were greater than their responses to stimulation of non-trigeminal receptive fields, and their responses to innocuous stimuli were induced only when applied to trigeminal receptive fields. As described for SHT axons, the axons of THT and RHT neurons ascended through the contralateral brain stem to the supraoptic decussation (SOD) in the lateral hypothalamus; 57% of them then crossed the midline to reach the ipsilateral hypothalamus. Collateral projections were found in the superior colliculus, substantia nigra, red nucleus, anterior pretectal nucleus, and in the lateral, perifornical, dorsomedial, suprachiasmatic, and supraoptic hypothalamic nuclei. Additional projections (which have not been described previously for SHT neurons) were found rostral to the hypothalamus in the caudate-putamen, globus pallidus, and substantia innominata. The findings that nonnociceptive signals reach the hypothalamus primarily through the direct THT route, whereas nociceptive signals reach the hypothalamus through both the direct THT and the indirect RHT routes suggest that highly prioritized painful signals are transferred in parallel channels to ensure that this critical information reaches the hypothalamus, a brain area that regulates homeostasis and other humoral responses required for the survival of the organism.

Instructed Delay Discharge in Primary and Secondary Somatosensory Cortex Within the Context of a Selective Attention Task

2009 ◽  
Vol 101 (5) ◽  
pp. 2649-2667 ◽  
Author(s):  
El-Mehdi Meftah ◽  
Stéphanie Bourgeon ◽  
C. Elaine Chapman
Keyword(s):  
Somatosensory Cortex ◽  
Recent Observation ◽  
Discharge Rate ◽  
Initial Response ◽  
Common Source ◽  
Attention Task ◽  
Secondary Somatosensory Cortex ◽  
Neuronal Mechanisms ◽  
Underlying Mechanisms ◽  
Cortical Regions

The neuronal mechanisms that contribute to tactile perception were studied using single-unit recordings from the cutaneous hand representation of primate primary (S1) and secondary (S2) somatosensory cortex. This study followed up on our recent observation that S1 and S2 neurons developed a sustained change in discharge during the instruction period of a directed-attention task. We determined the extent to which the symbolic light cues, which signaled the modality (tactile, visual) to attend and discriminate, elicited changes in discharge rate during the instructed delay (ID) period of the attention task and the functional importance of this discharge. ID responses, consisting of a sustained increase or decrease in discharge during the 2-s instruction period, were present in about 40% of the neurons in S1 and S2. ID responses in both cortical regions were very similar in most respects (frequency, sign, latency, amplitude), suggesting a common source. A major difference, however, was related to attentional modulation during the ID period: attentional influences were almost entirely restricted to S2 and these effects were always superimposed on the ID response (additive effect). These findings suggest that the underlying mechanisms for ID discharge and attention are independent. ID discharge significantly modified the initial response to the standard stimuli (competing texture and visual stimuli), usually enhancing responsiveness. We also showed that tactile detection in humans is enhanced during the ID period. Together, the results suggest that ID discharge represents a priming mechanism that prepares cortical areas to receive and process sensory inputs.

Peripheral Nerve Injury Alters the α2Adrenoceptor Subtype Activated by Clonidine for Analgesia

2002 ◽  
Vol 97 (3) ◽  
pp. 636-641 ◽  
Author(s):  
Frédéric Duflo ◽  
Xinhui Li ◽  
Carsten Bantel ◽  
Carlo Pancaro ◽  
Michelle Vincler ◽  
...  
Keyword(s):  
Nerve Injury ◽  
Antinociceptive Effect ◽  
Mechanical Stimulus ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Antisense Oligodeoxynucleotide ◽  
Alpha Adrenoceptors ◽  
Alpha Adrenoceptor ◽  
Withdrawal Threshold ◽  
Intrathecal Clonidine

Background Previous studies suggest that the alpha adrenoceptor subtype is the target for spinally administered alpha -adrenergic agonists, clonidine, for pain relief. However, ST 91, a preferential alpha adrenoceptor subtype agonist, induces antinociception, and intrathecally administered alpha antisense oligodeoxynucleotide decreases antinociception induced by clonidine in the rat, suggesting non-A sites may be important as well. Therefore, the authors examined the subtype of alpha adrenoceptor activated by clonidine and ST 91 in normal rats and those with nerve injury-induced hypersensitivity. Methods The same mechanical stimulus was applied to normal rats and those following spinal nerve ligation, and the effect of intrathecal clonidine and ST 91 on withdrawal threshold to the stimulus was determined. To further examine subtypes, animals were spinally pretreated with vehicle, BRL 44408 (an alpha subtype-preferring antagonist), and ARC 239 (an alpha subtype-preferring antagonist). Results In normal animals, clonidine's effect was diminished by pretreatment with either antagonist, whereas ST 91's antinociceptive effect was solely blocked by pretreatment with ARC 239. In nerve-injured animals, the antihypersensitivity action of both clonidine and ST 91 was blocked by administration of ARC 239, whereas BRL 44408 was ineffective. Conclusions These data agree with previous studies supporting that the alpha adrenoceptor is important to the antinociceptive effect of clonidine in normal animals. Nerve injury alters this and results in a total reliance on alpha adrenoceptors.

scholarly journals Neuronal hyperexcitability in the ventral posterior thalamus of neuropathic rats: modality selective effects of pregabalin

2016 ◽  
Vol 116 (1) ◽  
pp. 159-170 ◽  
Author(s):  
Ryan Patel ◽  
Anthony H. Dickenson
Keyword(s):  
Dynamic Range ◽  
Spinal Nerve ◽  
Population Coding ◽  
Mechanical Stimuli ◽  
Spinothalamic Tract ◽  
Noxious Heat ◽  
Posterior Thalamus ◽  
Central Processing ◽  
Wdr Neurons

Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex; however, under neuropathic conditions, it is unclear how hyperexcitability of spinal neurons converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurons in anesthetized spinal nerve-ligated (SNL), sham-operated, and naive rats. In neuropathic rats, WDR neurons had elevated evoked responses to low- and high-intensity punctate mechanical stimuli, dynamic brushing, and innocuous and noxious cooling, but less so to heat stimulation, of the receptive field. NS neurons in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling, and noxious heat. Additionally, WDR, but not NS, neurons in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR-to-NS neurons was comparable between SNL and naive/sham groups, suggesting relatively few NS neurons gain sensitivity to low-intensity stimuli leading to a “WDR phenotype.” After neuropathy was induced, the proportion of cold-sensitive WDR and NS neurons increased, supporting the suggestion that changes in frequency-dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold-evoked or elevated spontaneous activity.

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