Michael Tal's research while affiliated with Hebrew University of Jerusalem and other places

Publications (70)

Article
Ectopic discharge ("ectopia") in damaged afferent axons is a major contributor to chronic neuropathic pain. Clinical opinion discourages surgical resection of nerves proximal to the original injury site for fear of resurgence of ectopia and exacerbated pain. We tested this concept in a well-established animal neuroma model. Teased fiber recordings...
Article
Using a genetic model we demonstrate the role played by "phenotypic switching" of calcitonin gene related peptide (CGRP) expression in axotomized large Aβ afferents in the development of neuropathic pain behavior in rats. After nerve injury both substance P and CGRP are upregulated in Aβ afferents in the corresponding DRGs. It has been proposed tha...
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Full-text available
Loperamide reverses signs of mechanical hypersensitivity in an animal model of neuropathic pain suggesting that peripheral opioid receptors may be suitable targets for the treatment of neuropathic pain. Since little is known about loperamide effects on the responsiveness of primary afferent nerve fibers, in vivo electrophysiological recordings from...
Article
Pain is normally mediated by nociceptive Aδ and C fibers, while Aβ fibers signal touch. However, after nerve injury, Aβ fibers may signal pain. Using a genetic model, we tested the hypothesis that phenotypic switching in neurotransmitters expressed by Aβ afferents might account for heritable differences in neuropathic pain behavior. The study exami...
Article
Neuropathic pain is a chronic pain state resulting from peripheral nerve injury, characterized by hyperalgesia and allodynia. We have reported that mice with genetic impairment of IL-1 signaling display attenuated neuropathic pain behavior and ectopic neuronal activity. In order to substantiate the role of IL-1 in neuropathic pain, WT mice were imp...
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Full-text available
Chronic neuropathic pain is affected by specifics of the precipitating neural pathology, psychosocial factors, and by genetic predisposition. Little is known about the identity of predisposing genes. Using an integrative approach, we discovered that CACNG2 significantly affects susceptibility to chronic pain following nerve injury. CACNG2 encodes f...
Article
Inflammation along a nerve trunk (perineural inflammation), without detectable axonal damage, has been shown to induce transient pain in the organ supplied by the nerve. The aims of the present study were to study the role IL-6 and IL-1beta, in pain induced by perineural inflammation. IL-6 and IL-1beta secretion from rat's sciatic nerves, L-5 Dorsa...
Article
Propylisopropylacetamide (PID) is a chiral CNS-active constitutional isomer of valpromide, the amide derivative of the major antiepileptic drug valproic acid (VPA). The purpose of this work was: a) To evaluate enantiospecific activity of PID on tactile allodynia in the Chung (spinal nerve ligation, SNL) model of neuropathic pain in rats; b) To eval...
Article
Many neurotransmitters involved in pain perception transmit signals via G protein-coupled receptors (GPCRs). GPCR kinase 2 (GRK2) regulates agonist-induced desensitization and signaling of multiple GPCRs and interacts with downstream molecules with consequences for signaling. In general, low GRK2 levels are associated with increased responses to ag...
Article
Unlabelled: We studied the effects of topiramate at a relatively low dose of 20 mg/kg/d in rats that underwent chronic constriction injury (CCI) to the sciatic nerve. Fourteen rats underwent CCI and were then divided into two groups: one treated with topiramate and the other with an equal volume of saline. A further group of six rats was sham oper...
Article
Suggestion for hypnotic analgesia aimed at a specific body area is termed "focused hypnotic analgesia". It is not clear, however, whether this analgesia is limited to a specific body location or spread all over the body. Focused hypnotic analgesia was studied, in response to ascending electrical stimuli, when analgesia and stimulation were applied...
Article
Peripheral nerve injury may lead to neuropathic pain, which is often associated with mechanical and thermal allodynia, ectopic discharge of from injured nerves and from the dorsal root ganglion neurons, and elevated levels of proinflammatory cytokines, particularly interleukin-1 (IL-1). In the present study, we tested the role of IL-1 in neuropathi...
Article
To investigate the effect of jaw clenching on the sensations evoked at segmental and nonsegmental levels by painful and nonpainful stimuli and in relation to hypnotic susceptibility. The effect of jaw clenching on painful and nonpainful sensations on the face and leg was studied in high-hypnotizable (HH) and low-hypnotizable (LH) subjects. Sixteen...
Article
Cancer pain mechanisms involve multiple factors including the accompanying inflammatory process neural effects. Inflammation along a nerve trunk (neuritis) has been shown to induce hypersensitivity at the innervated target organ. In this experiment the neural effects of MAT B mammary adenocarcinoma cells implanted adjacent to sciatic nerve (MAT gro...
Article
Damage to peripheral nerves induces ectopic firing in sensory neurons, which can contribute to neuropathic pain. As most of the information on this topic is on dorsal root ganglia we decided to examine the influence of infra-orbital nerve section on cells of murine trigeminal ganglia. We characterized the electrophysiological properties of neurons...
Article
Experimental painful peripheral neuropathy induced by chronic constriction injury (CCI) of the sciatic nerve results in cutaneous thermal and mechanical allodynia of the hind limb. Our histological studies indicate that the major pathology in the CCI model is a loss of large diameter myelinated fibers distal to the site of injury. Electrophysiologi...
Article
This study was designed in order to examine the effects of different types of hypnotic suggestion on hypnotic analgesia. Generalized relaxation and focused analgesia were induced in seven high-hypnotizable (HH) and eight low-hypnotizable (LH) subjects. Subjects were not aware to which group they belonged. The two groups did not differ in their expe...
Article
In the facial region, chronic pain syndromes include musculoskeletal pain, neuropathic disorders, vascular pain, and other chronic headaches. Therapy of chronic facial pain syndromes often relies on long-term psychotropic medications that cause severe side effects and offer nontotal pain relief. In this article, therapeutically relevant advances in...
Article
Heat and electrical detection thresholds were assessed in 72 patients suffering from painful temporomandibular disorder. Employing widely accepted criteria, 44 patients were classified as suffering from temporomandibular joint (TMJ) arthralgia (i.e. pain originating from the TMJ) and 28 from myalgia (i.e. pain originating from the muscles of mastic...
Article
There is strong evidence for the presence of nucleotide (P2) receptors in sensory neurons, which might play a role in the transmission of pain signals. In contrast, virtually nothing is known about P2 receptors in satellite glial cells (SGCs), which are the main glial cells in sensory ganglia. We investigated the possibility that P2 receptors exist...
Article
We determined whether neural responses to inflammation and hyperalgesia involve activation of kainate receptors, a subgroup of glutamate receptors. Inflammation was introduced into the hind paw by intraplantar injection of complete Freund's adjuvant. The inflammation-induced thermal hyperalgesia was attenuated by intrathecal administration of a non...
Article
The present experiments investigated the behavioral and immunocytchemical (ICC) effects of applying complete Freund's adjuvant (CFA) to the orbital portion of the infraorbital nerve (IOn). Two control groups, the first had saline applied to the IOn and the second underwent sham operation, were included in the study. In the CFA group, significant hy...
Article
Full-text available
The present study examined the levels of NMDA receptor NR2 subunit tyrosine phosphorylation in a rat model of inflammation and correlated it with the development of inflammation and hyperalgesia. Hindpaw inflammation and hyperalgesia were induced by intraplantar injection of complete Freund's adjuvant. Proteins from the spinal cord (L4-L5) were imm...
Article
The aim of the present study was to test the behavioural effect of infraorbital (IO) chronic constriction injury (CCI) on the development of neuropathic pain in the rat hindpaw following sciatic nerve CCI performed 7 days later. Control groups consisted of rats that underwent sham infraorbital surgery followed by sciatic CCI at identical time point...
Article
Inflammation along a nerve trunk with no frank axonal nerve damage produced by complete Freund's adjuvant (CFA) or Carrageenan is known to induce a painful peripheral neuropathy. In the present study, we examined the electrophysiological properties of myelinated axons (spontaneous discharge and mechanical sensitivity) at the inflamed nerve site. Th...
Article
Following sciatic nerve injury sympathetic invasion and basket formation is seen in dorsal root ganglia. We examined whether this phenomenon occurs in trigeminal ganglion (TG) following axotomy (IOAx) or chronic constriction injury to the infraorbital nerve (IOCCI). The IOCCI rats developed hyperresponsiveness to pinprick stimulation consistent wit...
Article
Neuropathic pain is a disabling feature of peripheral nerve injury. Following injury, local inflammation and the release of mediators may contribute to ectopic mechanosensitivity of the nerve-trunk and pain hypersensitivity. In the present study we investigated whether nitric oxide (NO) action and local nitric oxide synthase (NOS) expression play a...
Article
Recent studies indicate that inflammatory events induced by nerve injury play a central role in the pathogenesis of neuropathic pain. These involve inflammatory cells (eg, macrophages), the production of molecules that mediate inflammation (cytokines/interleukins), and the production of nerve growth factor (NGF). However, in many instances, neuropa...
Article
It is difficult to know which afferent types preferentially develop ectopic firing characteristics following nerve injury because axotomy disconnects the sensory receptor ending from the remainder of the afferent neuron. We compared the prevalence of ectopic firing originating in nerve-end neuromas of nerves serving muscle and skin in the rat. Spon...
Article
We examined the relationship between hyperalgesia and degranulation of mast cells in rats following treatment with nerve growth factor (NGF) and inflammatory mediators. Intracutaneous injection to the rat's paw of NGF (50-5000 ng, 50 microl) evoked dose-dependent thermal hyperalgesia as measured by paw withdrawal latency to noxious heat. Even more...
Article
Rats with an experimental painful peripheral neuropathy (the chronic injury (CCI) model) display heatevoked hyperalgesia. There is now considerable evidence that nitric oxide (NO) and nitric oxide synthase are involved in the development of hyperalgesia in acute inflammatory pain states. The mechanisms responsible for hyperalgesia in chronic pain s...
Article
Rats with an experimental painful peripheral neuropathy created by placing loosely constrictive ligatures around the sciatic nerve (the CCI model) display heat-hyperalgesia on the affected limb. Pain threshold was studied using the paw withdrawal method. Electrophysiological recording from myelinated primary afferent axons revealed spontaneous impu...
Article
Rats with an experimental painful peripheral neuropathy (the CCI model) display heat-hyperalgesia and mechanoallodynia. Previous work has shown that the heat-hyperalgesia is suppressed by dextrorphan (DEX) and other N-methyl-D-aspartate (NMDA) receptor antagonists. The present work shows that when tested in the same rats, a dose of DEX that is maxi...
Article
The abnormal pain sensations that accompany peripheral neuropathies are sometimes found in a distribution that does not coincide with the territories of nerves or posterior roots. This 'extra-territorial' pain is one of the lines of evidence that has been advanced to support the proposal that these patients suffer from a psychogenic disorder. In th...
Article
Dextrorphan (DEX), a non-competitive NMDA receptor antagonist, was given intraperitoneally and intrathecally (i.t.) to rats with an experimental painful peripheral mononeuropathy. The neuropathy was created by placing loosely constrictive ligatures around the sciatic nerve, and the pain threshold was studied with the paw-flick method. The effects o...
Article
Microwire recordings from the histochemically heterogeneous inner compartment of the guinea pig anterior digastric muscle (ADG) revealed tonic firing of single motor units, which were spontaneously active and could also be recruited following orofacial afferent stimulation and during rhythmic jaw movements (RJM). As units with tonic firing were not...
Article
Using the teased fiber recording method, we have compared pathophysiological properties of afferent axons injured in the infraorbital nerve (ION) vs the sciatic nerve in rats. Both myelinated and unmyelinated axons ending in ION neuromas produced much less ongoing discharge than those ending in sciatic nerve neuromas. Similarly, mechanosensitivity...
Article
Sensations and masseter inhibitory periods (MIP) evoked by electrical tooth-pulp stimulation were recorded in 5 adults and 10 children. In the adult group there was always a sensation and it was usually associated with a two-phase MIP, with an early and a late component. Sensory detection in teeth with partially formed roots in the younger children...
Article
Amitriptyline, a tricyclic antidepressant (TCA), was effective in suppressing self-mutilation of a peripherally deafferented hind paw in rats ('autotomy'). This effect was not due to the drug's sedative effect, since locomotor activity was not lower in treated than untreated rats. Daily injections of normal saline also suppressed autotomy, but for...
Article
Sensation and masseter inhibitory periods (MIP) to electrical tooth-pulp stimulation were recorded under hypnotic anesthesia and placebo to local anesthesia. In the first experiment, 8 subjects were tested for the effect of hypnotic anesthesia on sensory detection and MIP at non-painful stimulus levels (mean = 42.1 microA) and painful levels (mean...
Article
Full-text available
The structure and activity patterns of the anterior and posterior heads of the guinea pig digastric muscle (DG) were studied in ketamine-anesthetized guinea pigs. Collagen staining of longitudinal and transverse sections of the muscle revealed that the guinea pig DG is comprised of a unicompartmental anterior head (ADG) and a multicompartmental pos...
Article
Our studies on the amphibian and mammalian motor systems suggest that sprouting of intact motoneurons and synapse formation can be regulated by three mechanisms: peripheral, central, and transneuronal. Peripheral mechanisms provide the means of a direct mode of interaction between the periphery of the nerve cell and the target, to determine the ext...
Article
The pattern of innervation to intact peroneal and extensor digitorum longus muscles of normal and experimental young adult mice was studied by light microscopy after staining neuromuscular junctions by a combined silver-cholinesterase stain. Spontaneous sprouting and synapse formation occur in intact muscles of normal mice. In about 7% of the junct...
Article
Electric stimulation was applied to the tooth-pulp and tongue in 12 children divided into 3 groups according to the development of the roots of the upper first incisors, i.e. 1/2, 3/4 and fully formed. The masseter inhibitory periods (MIP) could be evoked by electric stimulation of the tongue at sensory threshold current levels in all children, but...
Article
Full-text available
Injury to one cutaneous pectoris nerve of the frog induces sprouting of and synapse formation by the contralateral homologous intact nerve. It was previously suggested that axotomy initiates a signal for growth in the cell bodies of the injured motor neurons and that this signal is transferred transneuronally across the spinal cord to intact motor...
Article
The application of the myotoxic local anesthetic Carbocaine to the cutaneous-pectoris muscle of the frog produced muscle fiber degeneration. The degenerating muscle fibers were phagocytozed by macrophages leaving behind structurally intact motor nerve endings in close apposition to the sheath of basal lamina that normally surrounds muscle fibers. T...
Article
Marcaine, a long-acting local anaesthetic was administered subcutaneously over the rat's superficial masseter muscle. Rapid muscle fibre destruction with infiltration of mononuclear and polymorphonuclear leukocytes and degeneration of muscle fibers are the notable morphological changes following treatment with Marcaine. However, this degeneration w...
Article
Modulation of the jaw-opening reflex (JOR) by peripheral electrical stimulation was studied in the rat. The JOR was evoked by electrical stimuli delivered to the tongue, infraorbital nerve, or tooth pulp chamber, and single-pulse conditioning stimuli were delivered to the forelimb, hind limb, or tail. Threshold current for eliciting the JOR was mod...

Citations

... Although it is not possible to determine which fiber types are responsible for the heightened ectopic activity in our preparations, such ectopic discharge is likely to be responsible for spontaneous pain and paraesthesias. 50,51,60 We further identified an increased responsiveness to mechanical stimulation of AM and CM nociceptors characterized both by a reduced mechanical threshold and by an increased impulse discharge rate in response to supramaximal stimulation. It is likely that this increased peripheral drive gives rise to spinal sensitization, which would be consistent with the recent finding that spinal mechanisms involving interleukin-1b are engaged in tCRPS. ...
... This is supported by observational studies, which suggests clear comorbidity of chronic head-face-TMJ and neck pain [12]. From a pathobiological perspective, the strong overlap of COFP and headaches may be supported by the neuronal interplay of the trigeminal cervical complex in the brainstem and neuro-hormonal plasticity, which manifests itself in reaction to persistent injury and pain experiences [13,14]. Moreover, the head and the face are innervated by the trigeminal nerve cortex and connectomes (comprehensive map of neural connections in the brain) and in the somatosensory cortex an intimate overlap of these regions. ...
... [1][2][3] The various treatment modalities of painful neuromas remain controversial. [4][5][6] At this time, there is no consensus on the optimal treatment. However, it has been shown that surgical interventions can achieve meaningful clinical improvement of pain. ...
... 5-HT 1B and 5HT 1D auto-receptors on neural components, with 65% homology, do not permit more 5-HT production and discharge, and regulate the secretion of other mediators including substances that show pro-inflammatory impacts (Linde 2006). Anti-inflammatory properties of 5-HT 1B/1D receptors occur through reducing the release of neurotransmitters and neuropeptides (Nitzan-Luques et al. 2013). Moreover, existing records imply that sumatriptan has antiinflammatory properties by stimulating 5-HT 1B/1D receptors in rats (Dejban, Rahimi et al. 2019) and inhibiting TNF-α production (Arzt et al. 1991;Kubera et al. 2005). ...
... Mice were euthanized with 5% isoflurane in oxygen and cervical dislocation or decapitation. The hairy skin of the hind paw, together with the sural nerve, was carefully dissected and transferred to an in vitro system described previously [38,57]. The skin was mounted corium side up in an organ bath and superfused (10 mL/min) with synthetic interstitial fluid (SIF) heated to~32 • C and continuously bubbled with 95% oxygen/5% carbon dioxide to obtain a SIF pH of 7.4. ...
... Inflammation is a significant driver of both central and peripheral pain states (Chapman and Vierck, 2017;Gold and Gebhart, 2010;Ma et al., 2006;Price et al., 2018;Tal, 1999;Treede et al., 1992) and is often observed in the form of edema. To determine whether hindpaw edema was associated with inflammatory processes that developed during the acute phase of SCI, we measured paw thickness in a separate cohort of 10 naïve and 15 SCI mice during the first 7 days of recovery following SCI. ...
... 9-16 The jaw-opening reflex can be triggered by lowthreshold or high-threshold intraoral stimulation (e.g., of lingual nerve or tongue). 9,11,[13][14][15][16] The findings in animal studies of the effects of sleep on the amplitude of the reflex, however, are variable-some showing that the reflex excitability is reduced, others showing it is increased or unchanged during QS in comparison to QW. 9,11,18 Another approach to test motor excitability is to stimulate the corticobulbar pathways that activate brainstem motoneurons supplying the jaw muscles. Intracortical microstimulation Study Objective: To test the hypothesis that the reflex and corticobulbar motor excitability of jaw muscles is reduced during sleep. ...
... Primary sensory neuron excitability in vitro shown here provides a potential mechanism relevant to the block of chronic pain in the mouse model. The role of large-diameter neurons such as those implicated in cold sensing and Aβ nerve fibers are important in chronic pain behaviors including spontaneous pain and tactile allodynia [33][34][35]. The findings here imply the P2X4R scFv95 has potential to block phenotypic switching from acute to chronic pain. ...
... Degenerated IVDs or DDD models express significantly high levels of TNF-alpha and IL-1 beta. [21][22][23] Therefore, both these molecules are frequently used as IVD inflammatory stimulators in laboratory research. While IL-1 beta and TNF-alpha were initially thought to be secreted by inflammatory cells recruited to IVDs during degeneration, further studies in the 2000s discovered that disc cells also secrete these inflammatory cytokines. ...
... On the other hand, gene mapping, bioinformatics, microarray analysis, and human association analysis have led to the identification of CACNG2 as a gene that affects pain susceptibility in both mice and humans [89,90]. This gene encodes a protein called stargazin, a type 1a TARP, also known as the Ca V γ 2 subunit, which has been studied in the context of epilepsy [73,74]. ...