NK1 receptor-expressing spinoparabrachial neurons trigger diffuse noxious inhibitory controls through lateral parabrachial activation in the male rat

Diffuse noxious inhibitory controls (DNIC) are very powerful long-lasting descending inhibitory controls, which are pivotal in modulating the activity of spinal and trigeminal nociceptive neurons. The principal feature of DNIC is that they are subserved by a loop that involves supraspinal structures that have not yet been identified. Using behavioral, in vivo extracellular electrophysiological and anatomical approaches, we studied the neuronal network underlying DNIC. Using a new behavioral model of DNIC, in which facial grooming produced by formalin injection into the vibrissa pad is inhibited by a conditioning noxious stimulation, formalin injection into the hindpaw, we show that blockade of NK1 receptors in the lumbar spinal cord – by intrathecal administration of the NK1 receptor antagonist, RP67580 – largely attenuates DNIC-induced facial analgesia. In a second series of experiments, WDR neurons were recorded from the trigeminal subnucleus oralis and inhibited their C-fiber-evoked responses by the conditioning noxious heat stimulation of the hindpaw. We show that inactivating the lateral parabrachial area – by microinjecting the GABA_A agonist, muscimol – strongly attenuates DNIC-induced inhibition of C-fiber-evoked responses. Finally, our neuroanatomical tracing study demonstrates that the descending pathway for DNIC does not involve direct descending projections from the PB area. We conclude that (1) lamina I/III spinoparabrachial neurons that express the NK1 receptor and (2) parabrachial neurons are involved in the ascending part of the loop underlying DNIC and that the descending pathway for DNIC might include indirect projections to the spinal or medullary dorsal horn.     

Differential effects of the cannabinoid receptor agonist,WIN 55,212-2, on lamina I and lamina V spinal trigeminal nucleus caudalis neurons

Direct application of cannabinoids to the medullary dorsal horn (MDH) inhibits lamina V nociceptive neurons. The present study compared the effect of the cannabinoid receptor agonist, WIN 55,212-2 (WIN-2) on the activity of lamina I and lamina V MDH neurons using extracellular single unit recording in anesthetized rats. Activity evoked by a contact thermode was measured before and after local application of WIN-2 (0.5–2.0 μg/μl) to the brainstem. Fast and slow heat ramps were used to differentiate between activity evoked primarily by A-delta and C primary afferent fibers, respectively. In lamina V neurons, WIN-2 produced a concentration dependent decrease in activity evoked by both fast and slow heat, reaching significance at 1.0 μg/μl. In lamina I neurons, WIN-2 administration inhibited slow heat-evoked activity beginning at 1.0 μg/μl, but had no significant effect on fast heat-evoked activity, even at the highest concentration (2.0 μg/μl). In separate experiments, the effect of intrathecal administration of WIN-2 to the MDH on head withdrawal latencies elicited by fast and slow heat ramps applied to the whisker pad was assessed in lightly anesthetized rats. Head withdrawal latencies elicited by slow but not by fast heat stimulation were increased by WIN-2. Taken together, these results emphasize the importance of lamina I neurons in the control of a nociceptive heat-evoked reflex.     

An fMRI case report of photophobia: Activation of the trigeminal nociceptive pathway

Photophobia, or painful oversensitivity to light, occurs in a number of clinical conditions, which range from superficial eye irritation to meningitis. In this case study, a healthy subject with transient photophobia (induced by the overuse of contact lenses) was examined using functional magnetic resonance imaging (fMRI). While being scanned in a darkened environment, the subject was presented with intermittent 6-s blocks of bright light. The subject was scanned twice, once during his photophobic state and once after recovery. The subject reported that the visual stimuli produced pain (pain intensity = 3/10 and unpleasantness = 7/10) only during the photophobic state. During photophobia, specific activation patterns in the trigeminal system were seen at the level of the trigeminal ganglion, trigeminal nucleus caudalis, and ventroposteromedial thalamus. The anterior cingulate cortex, a brain structure associated with unpleasantness, was also active during photophobia. After recovery from photophobia, no significant activations were detected in these areas. This study may contribute to a better understanding of the pathways involved in photophobia in the human condition.     

Paraventricular oxytocinergic hypothalamic prevention or interruption of long-term potentiation in dorsal horn nociceptive neurons: Electrophysiological and behavioral evidence

Spinal long-term potentiation (LTP) elicited by noxious stimulation enhances the responsiveness of dorsal horn nociceptive neurons to their normal input, and may represent a key mechanism of central sensitization by which acute pain could turn into a chronic pain state. This study investigated the electrophysiological and behavioral consequences of the interactions between LTP and descending oxytocinergic antinociceptive mechanisms mediated by the hypothalamic paraventricular nucleus (PVN). PVN stimulation or intrathecal oxytocin (OT) reduced or prevented the ability of spinal LTP to facilitate selectively nociceptive-evoked responses of spinal wide dynamic range (WDR) neurons recorded in anesthetized rats. In a behavioral model developed to study the effects of spinal LTP on mechanical withdrawal thresholds in freely moving rats, the long-lasting LTP-mediated mechanical hyperalgesia was transiently interrupted or prevented by either PVN stimulation or intrathecal OT. LTP mediates long-lasting pain hypersensitivity that is strongly modulated by endogenous hypothalamic oxytocinergic descending controls.     

Compression of the trigeminal ganglion produces prolonged nociceptive behavior in rats

The present study is the first demonstration of prolonged nociceptive behavior in the trigeminal region following compression of the trigeminal ganglion in rats. Experiments were carried out on male Sprague–Dawley rats mounted onto a stereotaxic frame under pentobarbital sodium anesthesia. For compression of the trigeminal ganglion, a 4% agar solution (8μl) was injected into the trigeminal ganglion through a stainless steel injector (24 gauge), which extended 2mm beyond the end of a guide cannula (21 gauge). Following agar injection, the injector and guide cannula were removed. In the control group, rats were sham operated without agar injection. Air‐puff thresholds (mechanical allodynia), pin prick responses (mechanical hyperalgesia), and spontaneous scratching behavior were examined 3 days before surgery and at 3, 7, 10, 14, 17, 21, 24, 30, and 40 days after surgery. Data were analyzed using a repeated measures ANOVA followed by multiple group comparisons using the LSD post‐hoc test. Air‐puff thresholds significantly decreased after compression of the trigeminal ganglion. Mechanical allodynia was established within 3 days and lasted beyond postoperative day 24. Mechanical hyperalgesia was also evident 3 days after compression and persisted until the 40th postoperative day. Although mechanical allodynia and hyperalgesia appeared bilaterally, the ipsilateral side was significantly more sensitive. Intraperitoneal treatment with carbamazepine significantly blocked mechanical allodynia produced by compression of the trigeminal ganglion. These findings suggest that prolonged nociceptive behavior following compression of the trigeminal ganglion may mimic trigeminal neuralgia in this animal model.     

P2X3 receptor upregulation in trigeminal ganglion neurons through TNFα production in macrophages contributes to trigeminal neuropathic pain in rats

BackgroundTrigeminal neuralgia is a characteristic disease that manifests as orofacial phasic or continuous severe pain triggered by innocuous orofacial stimulation; its mechanisms are not fully understood. In this study, we established a new animal model of trigeminal neuralgia and investigated the role of P2X₃ receptor (P2X₃R) alteration in the trigeminal ganglion (TG) via tumor necrosis factor alpha (TNFα) signaling in persistent orofacial pain.MethodsTrigeminal nerve root compression (TNC) was performed in male Sprague-Dawley rats. Changes in the mechanical sensitivity of whisker pad skin, amount of TNFα in the TG, and number of P2X₃R and TNF receptor-2 (TNFR2)-positive TG neurons were assessed following TNC. The effects of TNFR2 antagonism in TG and subcutaneous P2X₃R antagonism on mechanical hypersensitivity following TNC were examined.ResultsTNC induced unilateral continuous orofacial mechanical allodynia, which was depressed by carbamazepine. The accumulation of macrophages showing amoeboid-like morphological changes and expression of TNFα in the TG was remarkably increased following TNC treatment. The number of P2X₃R- and TNFR2-positive TG neurons innervating the orofacial skin was significantly increased following TNC. TNFα was released from activated macrophages that occurred in the TG following TNC, and TNFR2 antagonism in the TG significantly diminished the TNC-induced increase in P2X₃R-immunoreactive TG neurons. Moreover, subcutaneous P2X₃R antagonism in the whisker pad skin significantly depressed TNC-induced mechanical allodynia.ConclusionsTherefore, it can be concluded that the signaling of TNFα released from activated macrophages in the TG induces the upregulation of P2X₃R expression in TG neurons innervating the orofacial region, resulting in orofacial mechanical allodynia following TNC.     

Estrogen status and psychophysical stress modify temporomandibular joint input to medullary dorsal horn neurons in a lamina-specific manner in female rats

Estrogen status and psychological stress contribute to the expression of several chronic pain conditions including temporomandibular muscle and joint disorders (TMJD). Sensory neurons that supply the temporomandibular joint (TMJ) region terminate in laminae I and V of the spinal trigeminal nucleus (Vc/C_1–2 region); however, little is known about lamina-specificity and environmental influences on the encoding properties of TMJ brainstem neurons. To test the hypothesis that Vc/C_1–2 neurons integrate both interoceptive and exteroceptive signals relevant for TMJ nociception, we recorded TMJ-evoked activity in superficial and deep laminae of ovariectomized rats under high and low estradiol (E2) and stress conditions. Rats received daily injections of low (LE) or high (HE) dose E2 and were subjected to forced swim (FS) or sham swim conditioning for 3 days. The results revealed marked lamina-specificity in that HE rats displayed enhanced TMJ-evoked activity in superficial, but not deep, laminae independent of stress conditioning. By contrast, FS conditioned rats displayed increased background firing and TMJ-evoked activity of neurons in deep, but not superficial, laminae independent of E2 status. FS also enhanced TMJ-evoked masseter muscle activity and suggested the importance of deep dorsal horn neurons in mediating evoked jaw muscle activity. In conclusion, E2 status and psychophysical stress play a significant role in modifying the encoding properties of TMJ-responsive medullary dorsal horn neurons with a marked lamina-specificity.     

Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission

Peripheral sensory ganglia contain somata of afferent fibres conveying somatosensory inputs to the central nervous system. Growing evidence suggests that the somatic/perisomatic region of sensory neurons can influence peripheral sensory transmission. Control of resting membrane potential (E_rest) is an important mechanism regulating excitability, but surprisingly little is known about how E_rest is regulated in sensory neuron somata or how changes in somatic/perisomatic E_rest affect peripheral sensory transmission. We first evaluated the influence of several major ion channels on E_rest in cultured small-diameter, mostly capsaicin-sensitive (presumed nociceptive) dorsal root ganglion (DRG) neurons. The strongest and most prevalent effect on E_rest was achieved by modulating M channels, K2P and 4-aminopiridine-sensitive K_V channels, while hyperpolarization-activated cyclic nucleotide-gated, voltage-gated Na⁺, and T-type Ca²⁺ channels to a lesser extent also contributed to E_rest. Second, we investigated how varying somatic/perisomatic membrane potential, by manipulating ion channels of sensory neurons within the DRG, affected peripheral nociceptive transmission in vivo. Acute focal application of M or K_ATP channel enhancers or a hyperpolarization-activated cyclic nucleotide-gated channel blocker to L5 DRG in vivo significantly alleviated pain induced by hind paw injection of bradykinin. Finally, we show with computational modelling how somatic/perisomatic hyperpolarization, in concert with the low-pass filtering properties of the t-junction within the DRG, can interfere with action potential propagation. Our study deciphers a complement of ion channels that sets the somatic E_rest of nociceptive neurons and provides strong evidence for a robust filtering role of the somatic and perisomatic compartments of peripheral nociceptive neuron.     

Severe burn injury induces a characteristic activation of extracellular signal‐regulated kinase 1/2 in spinal dorsal horn neurons

We have studied scalding‐type burn injury‐induced activation of extracellular signal‐regulated kinase 1/2 (ERK1/2) in the spinal dorsal horn, which is a recognised marker for spinal nociceptive processing. At 5 min after severe scalding injury to mouse hind‐paw, a substantial number of phosphorylated ERK1/2 (pERK1/2) immunopositive neurons were found in the ipsilateral dorsal horn. At 1 h post‐injury, the number of pERK1/2‐labelled neurons remained substantially the same. However, at 3 h post‐injury, a further increase in the number of labelled neurons was found on the ipsilateral side, while a remarkable increase in the number of labelled neurons on the contralateral side resulted in there being no significant difference between the extent of the labelling on both sides. By 6 h post‐injury, the number of labelled neurons was reduced on both sides without there being significant difference between the two sides. A similar pattern of severe scalding injury‐induced activation of ERK1/2 in spinal dorsal horn neurons over the same time‐course was found in mice which lacked the transient receptor potential type 1 receptor (TRPV1) except that the extent to which ERK1/2 was activated in the ipsilateral dorsal horn at 5 min post‐injury was significantly greater in wild‐type animals when compared to TRPV1 null animals. This difference in activation of ERK1/2 in spinal dorsal horn neurons was abolished within 1 h after injury, demonstrating that TRPV1 is not essential for the maintenance of ongoing spinal nociceptive processing in inflammatory pain conditions in mouse resulting from at least certain types of severe burn injury.     

Long term depression of human nociceptive skin senses induced by thin fibre stimulation.

We have recently shown that stimulation, through a multi-electrode array, of thin nerve fibres close to the dermo-epidermal junction in the skin, produces powerful inhibition of itch and, to a lesser degree, cutaneous pain in humans. Here, we have studied the induction time and frequency dependency (range 1-10Hz) of the inhibitory effects of such stimulation on itch, mechanical, and thermal pain, in 20 healthy subjects. Sixteen electrodes applied on the skin were consecutively stimulated using a method termed cutaneous field stimulation (CFS). The results show that different treatment periods with CFS were required for the induction of significant inhibitory effects on different nociceptive qualities: 1st heat pain (1 min), itch (3 min), 2nd heat pain (6 min), pinch evoked pain (8 min). Six to ten minutes stimulation sufficed to induce peak inhibitory effects on all these sensory qualities while longer stimulation (up to 40 min) did not cause significantly stronger inhibition. The effects on itch, 1st and 2nd heat pain lasted over 55 min after termination of CFS. There was no effect on prickle. No significant difference in inhibitory effects of different stimulation frequencies (1, 4 and 10Hz/electrode) was found. The induction time and effective stimulation frequencies may suggest that the underlying mechanisms are similar to those of long term depression (LTD) previously described in the spinal cord in animal experiments.     

Modulation of nociceptive and acoustic startle responses to an unpredictable threat in men and women

The present study examined whether a moderately aversive abdominal threat would lead to greater enhancement in affect- and pain-related defensive responding as indexed by the acoustic startle reflex (ASR) and nociceptive flexion reflex (NFR) in women compared to men. We also predicted sex differences in threat-related autonomic arousal measured by skin conductance responses (SCRs) to acoustic startle and noxious sural nerve stimulation. Unpredictable threat was manipulated by alternating 30-second safe (“no abdominal stimulation will be given”) and threat (“abdominal stimulation may occur at anytime”) periods. The experiment consisted of 2 blocks, each containing 4 safe and 4 threat periods in which the ASR or NFR was randomly probed 9-21 seconds following period onset. Unpredictable abdominal threat potentiated both ASR and NFR responses compared to periods signaling safety. SCRs to acoustic startle probes and noxious sural nerve stimulation were also significantly elevated during the threat vs safe periods. No sex differences in ASR or startle-evoked SCRs emerged. However, nociceptive responding was moderated by sex; females showed significant increases in NFR magnitudes across both safe and threat periods compared to males. Females also showed greater threat-potentiated SCRs to sural nerve stimulation than males. Our findings indicate that both affect- and pain-related defense and arousal systems are strongly influenced by threat of an aversive, unpredictable event, a situation associated with anticipatory anxiety. Females, compared to males, showed greater nociceptive responding and pain modulation when exposed to an unpredictable threatening context, whereas affect-driven ASR responses showed no such sex differentiation.     

NK-1 receptors in the rostral ventromedial medulla contribute to hyperalgesia produced by intraplantar injection of capsaicin

The rostral ventromedial medulla (RVM) is an area of the brainstem involved in the descending modulation of nociception at the level of the spinal cord. Although the RVM is involved in the inhibition or facilitation of nociception, the underlying mechanisms are not understood. Here we examined the role of the neuropeptide substance P and neurokinin-1 (NK-1) receptors located in the RVM on withdrawal responses evoked by mechanical and heat stimuli applied to the rat hindpaw under normal conditions and during hyperalgesia produced by capsaicin. The mechanical withdrawal threshold was obtained using von Frey monofilaments applied to the plantar surface of the hindpaw. Sensitivity to heat was determined by measuring the latency to withdrawal from radiant heat applied to the plantar surface. Mechanical and heat hyperalgesia were defined as a decrease in withdrawal response threshold or latency, respectively. Rats were prepared with a chronic cannula and either vehicle or the NK-1 receptor antagonists, L-733,060 or RP-67580, was injected into the RVM. Paw withdrawal responses were obtained before and after RVM injection, and then at 5, 30, and 60 min after an intraplantar injection of capsaicin (10 microg). Injection of the NK-1 antagonists at doses of 0.5 pmol or higher did not alter withdrawal responses to mechanical or heat stimuli under normal conditions but reduced the duration of nocifensive behavior and the mechanical and heat hyperalgesia produced by capsaicin. These findings suggest that the activation of NK-1 receptors in the RVM contributes to the hyperalgesia produced by capsaicin.     

射频热凝术对三叉神经痛患者疼痛及睡眠质量的影响

目的 探讨半月神经节射频热凝术对三叉神经痛患者疼痛的控制和睡眠质量的影响.方法 对30例三叉神经痛患者实施射频热凝术,采用视觉模拟量表(VAS)和匹兹堡睡眠质量指数量表(PSQI),分别于术前1 d、术后1个月进行疼痛强度和睡眠质量的评价.结果 本组术前VAS和PSQI总分分别为(8.57±0.68)分和(13.97±3.35),术后1个月分别为(1.77±1.48)分和(5.37±2.62)分,差异有统计学意义;手术前后疼痛与睡眠质量之间并非直接相关.结论 射频热凝术治疗三叉神经痛患者效果良好.     

Tonic and phasic descending dopaminergic controls of nociceptive transmission in the medullary dorsal horn

The transfer of nociceptive information at the level of dorsal horn is subject to extensive processing by both local segmental and supraspinal mechanisms, including descending dopaminergic controls, originating from the hypothalamic A11 nucleus. The inhibitory role of dopamine on evoked pain via activation of D2-like receptors at the level of the dorsal horn is well established. Here, by use of behavioral, electrophysiological, and anatomical techniques, we examined within the trigeminal sensory complex, first, whether descending dopaminergic controls also modulate pain behavior after an inflammatory insult, and second, under which physiological conditions these descending dopaminergic controls are actually recruited. We show that D2 receptors are mostly located within superficial medullary dorsal horn where trigeminal nociceptive fibers abut. Activating these D2-like receptors inhibits, whereas blocking them enhances, both formalin- and capsaicin-evoked pain behavior and C-fiber-evoked action potential firing of trigeminal wide dynamic range (WDR) neurons. Moreover, windup and diffuse noxious inhibitory controls (DNIC), 2 dynamic properties of C-fiber-evoked firing of WDR neurons, are inhibited by activating and blocking, respectively, these D2-like receptors. Altogether, our results are consistent with a tonic inhibition of the trigeminal nociceptive input by descending dopaminergic controls via activation of D2-like receptors at the level of superficial medullary dorsal horn. Such dopamine-dependent tonic inhibition of nociceptive information can be dynamically modulated by pain. This suggests that dysregulation of descending dopaminergic controls should translate in patients into diffuse, cephalic, and extracephalic pain symptoms—spontaneous pain, decreased pain thresholds, deficient DNIC, or some combination of these.     

Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control

Control of cancer, neuropathic, and postoperative pain is frequently inadequate or compromised by debilitating side effects. Inhibition or removal of certain nociceptive neurons, while retaining all other sensory modalities and motor function, would represent a new therapeutic approach to control severe pain. The enriched expression of transient receptor potential cation channel, subfamily V, member 1 (TRPV1; also known as the vanilloid receptor, VR1) in nociceptive neurons of the dorsal root and trigeminal ganglia allowed us to test this concept. Administration of the potent TRPV1 agonist resiniferatoxin (RTX) to neuronal perikarya induces calcium cytotoxicity by opening the TRPV1 ion channel and selectively ablates nociceptive neurons. This treatment blocks experimental inflammatory hyperalgesia and neurogenic inflammation in rats and naturally occurring cancer and debilitating arthritic pain in dogs. Sensations of touch, proprioception, and high-threshold mechanosensitive nociception, as well as locomotor function, remained intact in both species. In separate experiments directed at postoperative pain control, subcutaneous administration of RTX transiently disrupted nociceptive nerve endings, yielding reversible analgesia. In human dorsal root ganglion cultures, RTX induced a prolonged increase in intracellular calcium in vanilloid-sensitive neurons, while leaving other, adjacent neurons unaffected. The results suggest that nociceptive neuronal or nerve terminal deletion will be effective and broadly applicable as strategies for pain management.     

Involvement of solitary tract nucleus in control of nociceptive transmission in cat spinal cord neurons

In cats anesthetized with Nembutal and immobilized with Flaxedil, extracellular recordings were made from dorsal horn neurons and lamina X neurons in the lumbar spinal cord. The nociceptive responses of these neurons elicited by peripheral nerve stimulation were significantly inhibited by stimulation of the nucleus tractus solitarius (NTS) at low intensity without any noticeable cardiovascular reaction. As usual, the late response or C-response was found to be preferentially inhibited by NTS stimulation as compared with the early response or A-response. The effective current intensity for NTS stimulation-produced inhibition ranged from 80 μA to 200 μA. Stronger inhibition was induced when the stimulating site was within or in the immediate vicinity of the NTS. There was no significant difference in the efficacy of the NTS stimulation-produced inhibition of nociceptive response between dorsal horn neurons and lamina X neurons. A similar inhibitory effect was elicited by microinjection of monosodium glutamate into the NTS area.

The results demonstrate that the NTS may be involved in the control of nociceptive transmission at the spinal cord level.     

Serotonin increases the functional activity of capsaicin-sensitive rat trigeminal nociceptors via peripheral serotonin receptors

Peripheral serotonin (5HT) has been implicated in migraine and temporomandibular pain disorders in humans and animal models and yet the mechanism(s) by which 5HT evokes pain remains unclear. Trigeminal pain can be triggered by activation of the transient receptor potential V1 channel (TRPV1), expressed by a subset of nociceptive trigeminal ganglia (TG) neurons and gated by capsaicin, noxious heat, and other noxious stimuli. As 5HT is released in the periphery during inflammation and evokes thermal hyperalgesia, and TRPV1 is essential for thermal hyperalgesia, we hypothesized that 5HT increases the activity of capsaicin-sensitive trigeminal neurons and that this increase can be attenuated by pharmacologically targeting peripheral 5HT receptors. TG cultures were pretreated with 5HT (10 nM-100 μM), sumatriptan (5HT_1B/1D agonist), ketanserin (5HT_2A antagonist), granisetron (5HT₃ antagonist), or vehicle prior to capsaicin (30-50 nM). Single-cell accumulation of intracellular calcium was recorded or calcitonin gene-related peptide (CGRP) release was measured following each treatment. In addition, using in situ hybridization and immunohistochemistry, we detected the colocalization of 5HT_1B, 5HT_1D, 5HT_2A, and 5HT_3A, but not 5HT_2C mRNA with TRPV1 in TG cells. 5HT pretreatment evoked a significant increase in calcium accumulation in capsaicin-sensitive trigeminal neurons and enhanced capsaicin-evoked CGRP release, but had no significant effect when given alone. Sumatriptan, ketanserin, and granisetron treatment attenuated calcium accumulation and 5HT enhancement of capsaicin-evoked CGRP release. Together these results indicate that 5HT increases the activity of capsaicin-sensitive peripheral nociceptors, which can be attenuated by pharmacologically targeting peripheral 5HT receptors, thereby providing a mechanistic basis for peripheral craniofacial pain therapy.     

塞来昔布对骨关节炎大鼠疼痛评分和SP表达的影响

目的：探讨佐剂性诱导骨关节炎大鼠模型血清和脊髓背根神经节中SP表达变化,及其与痛觉评分的相关性和塞来昔布的干预效应。方法将40只SD大鼠随机分为4组：A组（正常组10只）、B组（正常＋塞来昔布组10只）、C组（骨关节炎组10只）、D组（骨关节炎＋塞来昔布组10只）,C和D组予以左膝和尾部皮内分别注射完全弗氏佐剂（CFA）诱导骨关节炎模型,通过酶联免疫吸附测定（ELISA）塞来昔布对于血浆和脊髓背根神经节内SP含量的影响,采用痛觉评分分析塞来昔布对骨关节炎后疼痛行为的影响。结果与对照组比较（A和B组）,骨关节炎大鼠模型（C和D组）脊髓和脊髓背根神经节内SP含量明显升高（P＜0.01）,且 SP 含量与疼痛疼痛评分呈正相关（r＝0.83,P＜0.01;r＝0.61,P＜0.01）;并且塞来昔布治疗组（D组）SP含量较C组显著降低（P＜0.05）。结论 SP在骨关节炎痛的发生中具有重要作用,塞来昔布抑制SP的合成或释放,从而缓解疼痛。     

Effects of substance P on nociceptive and non-nociceptive trigeminal brain stem neurons

As little information is available on the chemistry of synaptic transmission in trigeminal brain stem nuclei, an iontophoretic study was done on the effects of glutamate and substance P on single neurons in trigeminal nuclei oralis and caudalis in cats anesthetized with chloralose and paralyzed. The neurons were additionally studied for their responses to natural noxious and innocuous cutaneous and intraoral stimuli as well as to bipolar stimulation of the ipsilateral and contralateral canine tooth pulps, the exposed infraorbital and superior laryngeal nerves and forepaw. Glutamate excited all units tested. Substance P also had an excitatory effect, but only on some units. The slow time course of this effect was similar to that reported in other CNS regions. Units excited by substance P were located only in nucleus caudalis, and all responded to noxious cutaneous stimuli and/or to stimulation of tooth pulp; units responding only to innocuous orofacial stimulation were not excited by substance P. Levorphanol and opioid peptides were also applied iontophoretically to some of the neurons and were found to have depressant effects on nociceptive units. The data support the possibility that substance P and endogenous opioids play a role in chemical transmission in nociceptive pathways in trigeminal nucleus caudalis. The regional specificity of substance P excitation adds support to the earlier evidence of a differential distribution of sensory inputs to nuclei oralis vs. caudalis, with facial nocicpetive afferents projecting only to caudalis. The functional specificity of substance P excitation also adds to the parallels found between the dorsal horn and nucleus caudalis. In addition, the similarity between the dorsal horn and nucleus caudalis with respect to the effects of substance P and the opioids suggest a parallel in the neurochemistry of synaptic transmission at the two levels.     

Leveraging high-resolution 7-tesla MRI to derive quantitative metrics for the trigeminal nerve and subnuclei of limbic structures in trigeminal neuralgia

BackgroundTrigeminal Neuralgia (TN) is a chronic neurological disease that is strongly associated with neurovascular compression (NVC) of the trigeminal nerve near its root entry zone. The trigeminal nerve at the site of NVC has been extensively studied but limbic structures that are potentially involved in TN have not been adequately characterized. Specifically, the hippocampus is a stress-sensitive region which may be structurally impacted by chronic TN pain. As the center of the emotion-related network, the amygdala is closely related to stress regulation and may be associated with TN pain as well. The thalamus, which is involved in the trigeminal sensory pathway and nociception, may play a role in pain processing of TN. The objective of this study was to assess structural alterations in the trigeminal nerve and subregions of the hippocampus, amygdala, and thalamus in TN patients using ultra-high field MRI and examine quantitative differences in these structures compared with healthy controls.MethodsThirteen TN patients and 13 matched controls were scanned at 7-Tesla MRI with high resolution, T1-weighted imaging. Nerve cross sectional area (CSA) was measured and an automated algorithm was used to segment hippocampal, amygdaloid, and thalamic subregions. Nerve CSA and limbic structure subnuclei volumes were compared between TN patients and controls.ResultsCSA of the posterior cisternal nerve on the symptomatic side was smaller in patients (3.75 mm²) compared with side-matched controls (5.77 mm², p = 0.006). In TN patients, basal subnucleus amygdala volume (0.347 mm³) was reduced on the symptomatic side compared with controls (0.401 mm³, p = 0.025) and the paralaminar subnucleus volume (0.04 mm³) was also reduced on the symptomatic side compared with controls (0.05 mm³, p = 0.009). The central lateral thalamic subnucleus was larger in TN patients on both the symptomatic side (0.033 mm³) and asymptomatic side (0.035 mm³), compared with the corresponding sides in controls (0.025 mm³ on both sides, p = 0.048 and p = 0.003 respectively). The inferior and lateral pulvinar thalamic subnuclei were both reduced in TN patients on the symptomatic side (0.2 mm³ and 0.17 mm³ respectively) compared to controls (0.23 mm³, p = 0.04 and 0.18 mm³, p = 0.04 respectively). No significant findings were found in the hippocampal subfields analyzed.ConclusionsThese findings, generated through a highly sensitive 7 T MRI protocol, provide compelling support for the theory that TN neurobiology is a complex amalgamation of local structural changes within the trigeminal nerve and structural alterations in subnuclei of limbic structures directly and indirectly involved in nociception and pain processing.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01325-4.