The effect of neonatal capsaicin on the c-Fos-like immunoreactivity induced in subnucleus oralis neurons by noxious intraoral stimulation

The noxious stimulus-dependent induction of c-Fos-like immunoreactivity (Fos-LI) in neurons in the subnucleus oralis and the medullary dorsal horn (MDH) was significantly suppressed by the selective destruction of unmyelinated primary neurons. The induction of Fos-LI by topical capsaicin application to the lingual mucosal stimulation was almost completely suppressed by neonatal capsaicin treatment. Fos-LI induction by the tooth pulp stimulation and by formalin injection to the lingual mucosa were only partially reduced. These results provide an evidence that the noxious signals from the intraoral structures are transmitted by both unmyelinated and myelinated nociceptors to the subnucleus oralis as well as the MDH.     

Subtypes of nociceptive units in the rat temporomandibular joint

Response properties of nociceptors in the rat's temporomandibular joint (TMJ) were investigated using an in vitro TMJ-nerve preparation. Recordings were obtained from 33 nociceptive units that responded to mechanical, chemical, and/or thermal stimuli. According to both characteristics of nociceptors and afferent fibers, nociceptive units in the TMJ area were classified into the following four subtypes: Adelta-high-threshold mechanonociceptor (HTM) (12.1%), Adelta-polymodal nociceptor (POLY) (36.4%), C-HTM (12.1%), and C-POLY (39.4%). The mean mechanical threshold of the Adelta units was significantly lower than that of the C units. Bradykinin increased the discharge of Adelta- and C-POLY units. No significant differences of thermal thresholds between Adelta and C units were found. The percentage of Adelta units was 47.2% and of C units was 52.8%, respectively. In the TMJ area, POLY units were predominant (75.8%), suggesting that inflammatory reactions can easily evoke pain sensation.     

Does neurogenic inflammation alter the sensitivity of unmyelinated nociceptors in the rat?

This study on neurogenic inflammation aimed at comparing the effects of antidromic nerve stimulation and of cutaneous application of mustard oil on the mechanical and thermal sensitivity of cutaneous C-fibres in the rat saphenous nerve. They were tested with von Frey hairs and series of radiant heat stimuli in 5-min intervals before and after one of the above treatments. Antidromic electrical stimulation was effective in evoking a plasma extravasation in the saphenous region as revealed by prior intravenous injection of Evans blue. However, it did not evoke spontaneous activity in the polymodal C-fibres tested nor did it markedly affect their mechanical and thermal excitability in periods of up to 1 h after stimulation. Mustard oil, topically applied to the receptive fields, also evoked localized Evans blue extravasation and strongly affected the C-units. They responded to the application of the irritant with sustained firing; most units showed an increased thermal sensitivity after the treatment. This involved a lowering of the threshold and an increase of the suprathreshold discharge. Even low threshold mechanosensitive C-fibres transiently developed heat sensitivity. In some polymodal units a transient sensitization was followed by a persistent desensitization which abolished their thermal and mechanical sensitivity. Mustard oil application and antidromic nerve stimulation seem to be similar in evoking cutaneous vasodilatation and plasma extravasation but different in inducing nociceptor sensitization.     

Expert consensus of Chinese Association for the Study of Pain on the non-opioid analgesics for chronic musculoskeletal pain

Chronic musculoskeletal pain (CMP) is a common occurrence in clinical practice and there are a variety of options for the treatment of it. However, the pharmacological therapy is still considered to be a primary treatment. The recent years have witnessed the emergence of opioid crisis, yet there are no relevant guidelines on how to treat CMP with non-opioid analgesics properly. The Chinese Medical Association for the Study of Pain convened a panel meeting to develop clinical practice consensus for the treatment of CMP with non-opioid analgesics. The purpose of this consensus is to present the application of nonsteroidal anti-inflammatory drugs, serotonin norepinephrine reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, muscle relaxants, ion channel drugs and topical drugs in CMP.     

病理性疼痛的发生发展机制

疼痛不仅是一种伤害刺激引起机体的客观感觉,还是一种主观感受。所以疼痛的机制远比人们想象的要复杂。目前研究的重点在病理性疼痛,为了探究其产生及维持机制,以求找到治疗病理性疼痛的新靶点,许多学者做了深入的有成效的研究。本文就迄今为止关于病理性疼痛发生发展机制的研究进展作一综述。     

Sensitization of primary afferents to mechanical and heat stimuli after incision in a novel in vitro mouse glabrous skin-nerve preparation

In this study, we recorded activity from afferent fibers innervating the mouse plantar skin, the same region evaluated in pain behavior experiments. We compared responses of afferents from incised and unincised hind paw skin. The plantar skin together with attached medial and lateral plantar nerves was dissected until they could be completely removed intact and placed in an organ bath chamber continuously perfused with oxygenated Kreb’s solution with the temperature maintained at 32 °C. Afferent nerve activities to feedback-controlled mechanical and heat stimuli and cooling were recorded. Eighty-five single Aδ- and C-fiber afferents were recorded, 42 from control and the remainder from incised animals. A greater proportion of C-fibers (11/34) from incised skin had spontaneous activity than in the unincised preparation (2/32). The mechanical thresholds of both Aδ- and C-fiber units were not different between control and incised groups but the responses to suprathreshold mechanical stimulation were increased in low threshold Aδ- and C-fibers. The greatest change in heat sensitivity was apparent when multi-fiber total activity was measured; threshold was reduced, total spikes were greater and the peak discharge frequency was increased. In summary, feedback-controlled stimulation identified mechanical sensitization after incision in an in vitro preparation. Few fibers were excited by cooling. Heat sensitization of primary afferents was more prominent when activities of unclassified afferents are included. The preparation allows us to study afferent function of the same tissue that is examined for in vivo pain behavior assays in mice.     

Neurophysiological and biomechanical characterization of goat cervical facet joint capsules.

Cervical facet joints have been implicated as a major source of pain after whiplash injury. We sought to identify facet joint capsule receptors in the cervical spine and quantify their responses to capsular deformation. The response of mechanosensitive afferents in C5-C6 facet joint capsules to craniocaudal stretch (0.5 mm/s) was examined in anaesthetized adult goats. Capsular afferents were characterized into Group III and IV based on their conduction velocity. Two-dimensional strains across the capsules during stretch were obtained by a stereoimaging technique and finite element modeling. 17 (53%) Group III and 14 (56%) Group IV afferents were identified with low strain thresholds of 0.107+/-0.033 and 0.100+/-0.046. A subpopulation of low-strain-threshold afferents had discharge rate saturation at the strains of 0.388+/-0.121 (n=9, Group III) and 0.341+/-0.159 (n=9, Group IV). Two (8%) Group IV units responded only to high strains (0.460+/-0.170). 15 (47%) Group III and 9 (36%) Group IV units could not be excited even by noxious capsular stretch. Simple linear regressions were conducted with capsular load and principal strain as independent variables and neural response of low-strain-threshold afferents as the dependent variable. Correlation coefficients (R2) were 0.73+/-0.11 with load, and 0.82+/-0.12 with principal strain. The stiffness of the C5-C6 capsules was 16.8+/-11.4 N/mm. Our results indicate that sensory receptors in cervical facet joint capsules are not only capable of signaling a graded physiological mechanical stimulus, but may also elicit pain sensation under excessive deformation.     

Response properties of hypogastric afferent fibers supplying the uterus in the cat

The present study was undertaken to examine the sensory function of uterine afferent fibers in cats at unknown stages of the estrous cycle. Single unit activity was recorded from strands of the hypogastric nerve of the anesthetized cat. Once a unit was found, the conduction velocity was determined and the mechanical receptive field localized on the uterus. The response properties of the unit to mechanical stimuli applied to the receptive field and to chemical stimuli applied by intra-arterial injection of algesic chemicals (bradykinin, KCl and capsaicin) into the uterine artery were studied. Single unit activity from a total of 52 units was examined in this study. Based on the conduction velocities, about2/3 of these fibers were found to be unmyelinated C fibers and the remaining1/3 were thinly myelinated Aδ fibers. The receptive fields of most of these fibers were located at different parts of the uterine horn and body while a few were at the uterine cervix. Mechanical thresholds, as determined by von Frey filaments applied to the external surface of the uterus, varied more than 150-fold among mechanically sensitive units, ranging from extremely low to high thresholds. In addition, most of these afferents were activated by intra-arterially injected algesic chemicals, often by more than one chemical. The data in the present study suggest that a large portion of the cat uterus is innervated by the hypogastric nerve and that these afferents originate from sensory receptors that have potentially a wide range of functions. Their potential functions as low threshold mechanoreceptors and nociceptors are discussed.     

Partial nerve injury induces electrophysiological changes in conducting (uninjured) nociceptive and nonnociceptive DRG neurons: Possible relationships to aspects of peripheral neuropathic pain and paresthesias

Partial nerve injury leads to peripheral neuropathic pain. This injury results in conducting/uninterrupted (also called uninjured) sensory fibres, conducting through the damaged nerve alongside axotomised/degenerating fibres. In rats seven days after L5 spinal nerve axotomy (SNA) or modified-SNA (added loose-ligation of L4 spinal nerve with neuroinflammation-inducing chromic-gut), we investigated a) neuropathic pain behaviours and b) electrophysiological changes in conducting/uninterrupted L4 dorsal root ganglion (DRG) neurons with receptive fields (called: L4-receptive-field-neurons). Compared to pretreatment, modified-SNA rats showed highly significant increases in spontaneous-foot-lifting duration, mechanical-hypersensitivity/allodynia, and heat-hypersensitivity/hyperalgesia, that were significantly greater than after SNA, especially spontaneous-foot-lifting. We recorded intracellularly in vivo from normal L4/L5 DRG neurons and ipsilateral L4-receptive-field-neurons. After SNA or modified-SNA, L4-receptive-field-neurons showed the following: a) increased percentages of C-, Ad-, and Ab-nociceptors and cutaneous Aa/b-low-threshold mechanoreceptors with ongoing/spontaneous firing; b) spontaneous firing in C-nociceptors that originated peripherally; this was at a faster rate in modified-SNA than SNA; c) decreased electrical thresholds in A-nociceptors after SNA; d) hyperpolarised membrane potentials in A-nociceptors and Aa/b-low-threshold-mechanoreceptors after SNA, but not C-nociceptors; e) decreased somatic action potential rise times in C- and A-nociceptors, not Aa/b-low-threshold-mechanoreceptors. We suggest that these changes in subtypes of conducting/uninterrupted neurons after partial nerve injury contribute to the different aspects of neuropathic pain as follows: spontaneous firing in nociceptors to ongoing/spontaneous pain; spontaneous firing in Aa/b-low-threshold-mechanoreceptors to dysesthesias/paresthesias; and lowered A-nociceptor electrical thresholds to A-nociceptor sensitization, and greater evoked pain.     

Functional interactions between NMDA receptors and TRPV1 in trigeminal sensory neurons mediate mechanical hyperalgesia in the rat masseter muscle

The NMDA and TRPV1 receptors that are expressed in sensory neurons have been independently demonstrated to play important roles in peripheral pain mechanisms. In the present study, we investigated whether the 2 receptor-channel systems form a functional complex that provides the basis for the development of mechanical hyperalgesia. In the masseter muscle, direct application of NMDA induced a time-dependent increase in mechanical sensitivity, which was significantly blocked when the muscle was pretreated with a specific TRPV1 antagonist, AMG9810. The NR1 subunit of the NMDA receptor and TRPV1 were coexpressed in 32% of masseter afferents in trigeminal ganglia (TG). Furthermore, NR1 and NR2B formed protein-protein complexes with TRPV1 in TG as demonstrated by coimmunoprecipitation experiments. Calcium imaging analyses further corroborated that NMDA and TRPV1 receptors functionally interact. In TG culture, application of NMDA resulted in phosphorylation of serine, but not threonine or tyrosine, residues of TRPV1 in a time course similar to that of the development of NMDA-induced mechanical hyperalgesia. The NMDA-induced phosphorylation was significantly attenuated by CaMKII and PKC inhibitors, but not by a PKA inhibitor. Consistent with the biochemical data, the NMDA-induced mechanical hyperalgesia was also effectively blocked when the muscle was pretreated with a CaMKII or PKC inhibitor. Thus, NMDA receptors and TRPV1 functionally interact via CaMKII and PKC signaling cascades and contribute to mechanical hyperalgesia. These data offer novel mechanisms by which 2 ligand-gated channels in sensory neurons interact and reinforce the notion that TRPV1 functions as a signal integrator under pathological conditions.