Radi Masri

Zona Incerta: A Role in Central Pain

Central pain syndrome (CPS) is a debilitating condition that affects a large number of patients with a primary lesion or dysfunction in the CNS. Despite its discovery over a century ago, the pathophysiological processes underlying the development and maintenance of CPS are poorly understood. We recently demonstrated that activity in the posterior thalamus (PO) is tightly regulated by inhibitory inputs from zona incerta (ZI). Here we test the hypothesis that CPS is associated with abnormal inhibitory regulation of PO by ZI. We recorded single units from ZI and PO in animals with CPS resulting from spinal cord lesions. Consistent with our hypothesis, the spontaneous firing rate and somatosensory evoked responses of ZI neurons were lower in lesioned animals compared with sham-operated controls. In PO, neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses to noxious and innocuous stimuli applied to the hindpaw and to the face. These changes were not associated with increased afferent drive from the spinal trigeminal nucleus or changes in the ventroposterior thalamus. Thus CPS can result from suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus.

Conditioned Place Preference Reveals Tonic Pain in an Animal Model of Central Pain

UNLABELLED A limitation of animal models of central pain is their inability to recapitulate all clinical characteristics of the human condition. Specifically, many animal models rely on reflexive measures of hypersensitivity and ignore, or cannot assess, spontaneous pain, the hallmark characteristic of central pain in humans. Here, we adopt a conditioned place preference paradigm to test if animals with lesions in the anterolateral quadrant of the spinal cord develop signs consistent with spontaneous pain. This paradigm relies on the fact that pain relief is rewarding to animals, and has been used previously to show that animals with peripheral nerve injury develop tonic pain. With the use of 2 analgesic treatments commonly used to treat patients with central pain (clonidine infusion and motor cortex stimulation), we demonstrate that analgesic treatments are rewarding to animals with spinal cord lesions but not sham-operated controls. These findings are consistent with the conclusion that animals with spinal cord injury suffer from tonic pain. PERSPECTIVE The hallmark characteristic of central pain in humans is spontaneous pain. Animal models of central pain rely on reflexive measures of hypersensitivity and do not assess spontaneous pain. Demonstrating that animals with spinal cord injury suffer from tonic pain is important to study the etiology of central pain.

Motor Cortex Stimulation Reduces Hyperalgesia in an Animal Model of Central Pain

&NA; Electrical stimulation of the primary motor cortex has been used since 1991 to treat chronic neuropathic pain. Since its inception, motor cortex stimulation (MCS) treatment has had varied clinical outcomes. Until this point, there has not been a systematic study of the stimulation parameters that most effectively treat chronic pain, or of the mechanisms by which MCS relieves pain. Here, using a rodent model of central pain, we perform a systematic study of stimulation parameters used for MCS and investigate the mechanisms by which MCS reduces hyperalgesia. Specifically, we study the role of the inhibitory nucleus zona incerta (ZI) in mediating the analgesic effects of MCS. In animals with mechanical and thermal hyperalgesia, we find that stimulation at 50 μA, 50 Hz, and 300 μs square pulses for 30 minutes is sufficient to reverse mechanical and thermal hyperalgesia. We also find that stimulation of the ZI mimics the effects of MCS and that reversible inactivation of ZI blocks the effects of MCS. These findings suggest that the reduction of hyperalgesia may be due to MCS effects on ZI. In an animal model of central pain syndrome, motor cortex stimulation reduces hyperalgesia by activating zona incerta and therefore restoring inhibition in the thalamus.

The change in retentive values of locator attachments and hader clips over time.

PURPOSE The aim of this study was to examine early changes in retentive values of implant overdenture attachments during multiple pulls. MATERIALS AND METHODS Two implant attachment systems (Hader bar and clip, Locator system) were used in this study. The experimental groups were divided into yellow Hader clips, white Locator attachments, and green Locator attachments. Each group consisted of 21 matrix attachments. The attachments were placed into a custom-made acrylic resin block seated passively on another acrylic block containing a Hader bar or two Locator abutments with different angulations. Each attachment was subjected to 20 consecutive pulls using a universal testing machine. The peak load-to-dislodgement of the attachments after each pull was documented, and the percent reduction of the peak load-to-dislodgement was calculated. One-way ANOVA and Tukeys honestly significant difference test were used for data analyses. A p < or = 0.05 was considered significant. RESULTS There was a significant difference in the percent reduction in peak load-to-dislodgement between the attachments after the first pull (p= 0.005) and after the final pull (p= 0.0001). The yellow Hader clips exhibited the least percent reduction in peak load-to-dislodgement (6.50 +/- 3.59%) after the first pull, followed by the white Locator attachments (8.60 +/- 4.42%); the green Locator attachments exhibited the greatest reduction (11.05 +/- 4.94%). CONCLUSION The results of this in vitro study demonstrate that retentive values of the Locator attachments are reduced significantly after multiple pulls. Although this reduction might not be noticeable to the patient, it is recommended that the clinician place and remove the overdenture multiple times before delivery.

Development of a behavioral assessment of craniofacial muscle pain in lightly anesthetized rats

&NA; In this study, a new behavioral assessment of craniofacial muscle pain in the lightly anesthetized rat is described. Intramuscular injections with algesic agents in lightly anesthetized rats evoked a characteristic ipsilateral hindpaw shaking behavior for several minutes similar to previously described orofacial pain‐induced grooming behavior in awake rats (Neurosci Lett 103 (1989) 349, Pain 62 (1995) 295). Eighty‐two male Sprague–Dawley rats were used in a series of experiments to study whether this behavior could serve as a valid measure of craniofacial muscle pain. First, we demonstrated that different algesic chemicals, mustard oil (20%), formalin (3%) or hypertonic saline (5%) injected in the mid‐region of the masseter muscle effectively elicited the hindpaw shaking behavior. The behavior was only minimally evoked with vehicle injection. Repeated administrations of hypertonic saline, a short duration non‐sensitizing algogen, demonstrated reproducibility of the assay. Second, we showed that the peak and overall magnitude of the shaking behavior evoked by injections with different concentrations of mustard oil (1 and 5%) changed in a concentration dependent manner. Finally, we showed that systemic administration of morphine sulfate (3 and 0.3 mg/kg, i.p.) dose dependently attenuated mustard oil induced hindpaw‐shaking behavior. Lidocaine injected locally 5 min prior to mustard oil injection also significantly decreased the hindpaw shaking behavior. Based on these results we concluded that ipsilateral hindpaw shaking in lightly anesthetized rats is a stereotypical behavior evoked by noxious muscle stimulation and can be used as a reliable behavioral measure to assess craniofacial muscle pain.

Encoding of Stimulus Frequency and Sensor Motion in the Posterior Medial Thalamic Nucleus

In all sensory systems, information is processed along several parallel streams. In the vibrissa-to-barrel cortex system, these include the lemniscal system and the lesser-known paralemniscal system. The posterior medial nucleus (POm) is the thalamic structure associated with the latter pathway. Previous studies suggested that POm response latencies are positively correlated with stimulation frequency and negatively correlated with response duration, providing a basis for a phase locked loop-temporal decoding of stimulus frequency. We tested this hypothesis by analyzing response latencies of POm neurons, in both awake and anesthetized rats, to vibrissae deflections at frequencies between 0.3 and 11 Hz. We found no significant, systematic correlation between stimulation frequency and the latency or duration of POm responses. We obtained similar findings from recording in awake rats, in rats under different anesthetics, and in anesthetized rats in which the reticular activating system was stimulated. These findings suggest that stimulus frequency is not reliably reflected in response latency of POm neurons. We also tested the hypothesis that POm neurons respond preferentially to sensor motion, that is, they respond to whisking in air, without contacts. We recorded from awake, head-restrained rats while monitoring vibrissae movements. All POm neurons responded to passive whisker deflections, but none responded to noncontact whisking. Thus like their counterparts in the trigeminal ganglion, POm neurons may not reliably encode whisking kinematics. These observations suggest that POm neurons might not faithfully encode vibrissae inputs to provide reliable information on vibrissae movements or contacts.

The effect of experimental muscle pain on the amplitude and velocity sensitivity of jaw closing muscle spindle afferents

The effect of experimental muscle pain on the amplitude and velocity sensitivity of muscle spindle primary afferent neurons in the trigeminal mesencephalic nucleus (Vmes) was examined. Extracellular recordings were made from 45 neurons designated as spindle primary- or secondary-like on the basis of their response to ramp-and-hold jaw movements. Velocity sensitivity was assessed in spindle primary-like afferents by calculating the mean dynamic index of each unit in response to three different velocities of jaw opening before and after intramuscular injection with hypertonic saline (HS, 5%, 100 microl). The amplitude sensitivity of all jaw muscle spindle afferents was assessed by calculating the mean firing rate of each unit in response to three different amplitudes of jaw openings during both the open and hold phases of the movement and with best-fit lines obtained, using linear regression analysis, before and after HS injection. The variance of the two regression lines obtained for each unit before and after the injection was compared using the coincidence test, and changes in intercept and slope were determined. Seventy-five percent of the primary-like units and 80% of the secondary-like units presented with changes in static behavior after HS injection. Thirty-six percent of the primary-like units showed changes in dynamic behavior. Injection of isotonic saline (control) did not alter the responses of the spindle afferent to jaw opening. Thus, our results demonstrate that the predominant effect of noxious stimulation was a shift in the amplitude sensitivity of both spindle primary-like and secondary-like afferents and, to a lesser extent, the velocity sensitivity of the spindle primary-like unit. In accordance with earlier studies in the cat hindlimb and neck muscles, these results suggest that the activation of masseter muscle nociceptor alters spindle afferent responses to stretch acting primarily through static gamma motor neurons.

Abnormal activity of primary somatosensory cortex in central pain syndrome.

Central pain syndrome (CPS) is a debilitating and chronic pain condition that results from a lesion or dysfunction in the CNS. The pathophysiological mechanisms underlying CPS are poorly understood. We recently demonstrated that CPS is associated with suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus (PO). As a consequence, activity in PO is abnormally increased in CPS. Because the perception of pain requires activity in the cerebral cortex, CPS must also involve abnormal cortical activity. Here we test the hypothesis that CPS is associated with increased activity in the primary somatosensory cortex (SI), a major projection target of PO that plays an important role in processing sensory-discriminative aspects of pain. We recorded activity of single units in SI in rats with CPS resulting from spinal cord lesions. Consistent with our hypothesis, SI neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses evoked by innocuous and noxious mechanical stimulation of the hindpaw compared with control rats. Neurons from lesioned rats also showed a greater tendency than controls to fire bursts of action potentials in response to noxious stimuli. Thus, the excruciatingly painful symptoms of CPS may result, at least in part, from abnormally increased activity in SI.

The effect of denture cleansing solutions on the retention of pink Locator attachments: an in vitro study.

PURPOSE To evaluate the changes in retention of pink Locator attachments after exposure to various denture cleansers. MATERIALS AND METHODS Six groups (20 pairs each) of pink Locator attachments (3.0 lb. Light Retention replacement patrix attachments) were soaked for the equivalent of 6 months of clinical use in the following solutions: Water (control), Polident Regular, Efferdent, 6.15% sodium hypochlorite (NaOCL, 1:10 dilution), Polident Overnight, and Cool Mint Listerine mouthwash. A universal testing machine set at a crosshead speed of 2 in/min was used to perform one pull. The peak load-to-dislodgement was recorded to reflect changes in the retention of the Locator attachments after soaking. Data were analyzed by one-way ANOVA followed by Tukeys Honestly Significant Difference test. A p< or = 0.05 was considered significant. RESULTS Denture cleansing solutions significantly affected the retentive values of pink Locator attachments (F = 344.3, p< or = 0.0001). Cool Mint Listerine mouthwash increased the retentive values of the attachments (51.10 +/- 5.31 N) when compared to the control group (45.25 +/- 3.49 N). There was no significant difference in the retentive values of attachments soaked in Polident Regular or Polident Overnight when compared to the control group. Efferdent caused a small reduction in the retentive values (40.81 +/- 2.56 N) and most importantly, diluted NaOCl caused a large reduction in the retentive values (7.83 +/- 2.50 N) of pink Locator attachments. In addition, Cool Mint Listerine mouthwash caused blue discoloration of the Locator attachments, and NaOCl caused whitening and softening of the pink Locator attachments. CONCLUSION Cool Mint Listerine and Efferdents small effect on the retentive values of the Locators might be clinically unimportant; however, NaOCl caused a large reduction in the retentive values of the attachments. Because of their effect on retentive values and on the color of the Locator attachments, NaOCl and Cool Mint Listerine are not recommended. These results should be interpreted clinically with caution, realizing that different results may be obtained when fatigue stress during function and multiple pulls (in vivo) are combined with the chemical action of denture cleansers.

Hypertonic saline‐induced muscle nociception and c‐fos activation are partially mediated by peripheral NMDA receptors

In this study, the animal model of hypertonic saline (HS) infusion protocol was developed and utilized to test the hypothesis that HS causes peripheral release of glutamate, and that blockade of peripheral NMDA receptors significantly reduces HS‐induced nocifensive behavior and central neuronal activation. Nocifensive behavior and c‐fos immunoreactivity, as a marker of central neuronal activation, were assessed from the animals that received intramuscular HS infusion with and without the NMDA receptor antagonist, MK‐801. HS infusion (20μl/min for 10min) in the rat masseter produced prolonged nocifensive hindpaw shaking responses that peaked in the first minute and gradually diminished over the infusion period. The HS induced nocifensive behavior was dose‐dependently attenuated by MK‐801 pretreatments (0.3mg/kg and 0.1mg/kg), but not by vehicle pretreatment (isotonic saline; ISO), in the masseter muscle. HS infusion produced a significant number of Fos positive neurons in the ispsilateral subnucleus caudalis (Vc). Subsequent immunohistochemical studies showed that peripheral MK‐801 pretreatment effectively reduced the HS induced neuronal activation in the Vc. These results provide compelling evidence that HS‐induced muscle nociception is mediated, in part, by peripheral release of glutamate, and that blockade of peripheral glutamate receptors may provide effective means of preventing central neuronal activation.