Patent Application: US-69991810-A

Abstract:
central pain syndrome is a debilitating condition that affects a large number of patients with a primary lesion or dysfunction in the central nervous system . despite its discovery over a century ago , the pathophysiology underlying the development and maintenance of cps is poorly understood . the present invention is drawn to novel methods of treating cps . in certain aspects , the invention is drawn to the novel discovery of the role of the zona incerta in cps and methods of exploiting this novel discovery for the treatment of cps .

Description:
unless otherwise noted , technical terms are used according to conventional usage . definitions of common terms in molecular biology may be found , for example , in benjamin lewin , genes vii , published by oxford university press , 2000 ( isbn 019879276x ); kendrew et al . ( eds . ); the encyclopedia of molecular biology , published by blackwell publishers , 1994 ( isbn 0632021829 ); and robert a . meyers ( ed . ), molecular biology and biotechnology : a comprehensive desk reference , published by wiley , john & amp ; sons , inc ., 1995 ( isbn 0471186341 ); and other similar technical references . as used herein , “ a ” or “ an ” may mean one or more . as used herein when used in conjunction with the word “ comprising ,” the words “ a ” or “ an ” may mean one or more than one . as used herein “ another ” may mean at least a second or more . furthermore , unless otherwise required by context , singular terms include pluralities and plural terms include the singular . as used herein , “ about ” refers to a numeric value , including , for example , whole numbers , fractions , and percentages , whether or not explicitly indicated . the term “ about ” generally refers to a range of numerical values ( e . g ., +/− 5 - 10 % of the recited value ) that one of ordinary skill in the art would consider equivalent to the recited value ( e . g ., having the same function or result ). in some instances , the term “ about ” may include numerical values that are rounded to the nearest significant figure . as used herein , “ treat ” and all its forms and tenses ( including , for example , treat , treating , treated , and treatment ) refer to therapeutic treatment , prophylactic or preventative treatment , and management of a pathological condition of the invention ( including , for example , cps , hyperalgesia , and allodynia ). an individual in need thereof of treatment include those already with a pathological condition of the invention ( including , for example , cps , hyperalgesia , and allodynia ) as well as those in which a pathological condition of the invention is to be prevented or managed . the rat model used in our study ( wang and thompson , 2008a ) recapitulates several diagnostic signs of cps . immediately following spinal lesions that involve the spinothalamic tract ( stt ), the rats display transient mechanical hypoalgesia below and unilateral to the lesion , and , within two to three weeks , they developed bilateral hyperalgesia below the lesion . in addition , cold hyperalgesia appeared within 14 days in the hindpaw ipsilateral to the lesion . the time course of these changes , the presence of bilateral mechanical hyperalgesia , and the reversal of hyperalgesia by a centrally acting opiate , are all consistent with pathophysiology in supraspinal structures . all rats that developed cps had lesions within the stt , consistent with the obligatory role of insults to the spinothalamocortical pathway in the pathophysiology of cps ( canavero and bonicalzi , 2007 ). support for a role of supraspinal pathophysiology comes from the finding that activity in two major targets of the stt , the spinal trigeminal nucleus , a main source of afferent inputs to the po , and the vpl , were unaffected by spinal lesions . the inventors cannot exclude the possibility that the lesions affected other spinal nuclei or ascending and descending tracts , or the possibility that damage to these regions might contribute to the clinical signs of cps . nevertheless , regardless of the precipitating insult , this model provides clear evidence of the role that the zi and the po occupy in the pathophysiology of cps . the zi sends a dense gabaergic projection to the posterior nucleus of the thalamus ( po ) ( power et al ., 1999 ; bartho et al ., 2002 ), a nucleus critically involved in nociceptive processing ( poggio and mountcastle , 1960 ; casey , 1966 ; apkarian and shi , 1994 ; zhang and giesler , 2005 ). in certain aspects of the invention , the zi is stimulated directly by electrical stimulation , which causes , for example , an increase in gabaergic neuron firing ( including , for example , gabaergic neurons projecting to the po ). in other aspects of the invention , the zi is stimulated indirectly by stimulating another brain region or nucleus which causes , for example , an increase in zi gabaergic neuron firing ( including , for example , gabaergic neurons projecting to the po ). indirect stimulation can be achieved , for example , by electrically stimulating the motor cortex , which causes stimulation of the zi . indirect stimulation can be achieved either electrically or by the administration of a molecule with biological activity . electrical stimulation encompassed by the instant invention is any amount of electrical stimulation that can increase the firing rate of zi neurons ( including , for example , gabaergic neurons projecting to the po ) or decrease the firing rate of po neurons . this can be achieved by , for example , direct electrical stimulation ( or indirect stimulation resulting in the equivalent ) of the zi at a frequency range of 0 . 1 hz to 1000 hz , intensity range of 1 μa to 1 ma , or any combination therein . both long trains of stimuli , or patterned stimuli ( including , for example , theta burst stimulation ) can be used . in certain aspects of the invention , the frequency range is between about 0 . 1 hz to 900 hz , 0 . 1 hz to 800 hz , 0 . 1 hz to 700 hz , 0 . 1 hz to 600 hz , 0 . 1 hz to 500 hz , 0 . 1 hz to 400 hz , 0 . 1 hz to 300 hz , 0 . 1 hz to 200 hz , 0 . 1 hz to 100 hz , 1 hz to 900 hz , 1 hz to 800 hz , 1 hz to 700 hz , 1 hz to 600 hz , 1 hz to 500 hz , 1 hz to 400 hz , 1 hz to 300 hz , 1 hz to 200 hz , 1 hz to 100 hz , 10 hz to 100 hz , 20 hz to 100 hz , 30 hz to 100 hz , 40 hz to 100 hz , 50 hz to 100 hz , 60 hz to 100 hz , 70 hz to 100 hz , 80 hz to 100 hz , and 90 hz to 100 hz . in further certain aspects of the invention , the frequency range is between about 25 hz to 75 hz , 30 hz to 70 hz , 35 hz to 65 hz , 40 hz to 60 hz , and 45 hz to 55 hz . in other certain aspects of the invention , the intensity range is between about 1 μa to 0 . 9 ma , 1 μa to 0 . 8 ma , 1 μa to 0 . 7 ma , 1 μa to 0 . 6 ma , 1 μa to 0 . 5 ma , 1 μa to 0 . 4 ma , 1 μa to 0 . 3 ma , 1 μa to 0 . 2 ma , 1 μa to 0 . 1 ma , 1 μa to 0 . 09 ma , 1 μa to 0 . 08 ma , 1 μa to 0 . 07 ma , 1 μa to 0 . 06 ma , 1 μa to 0 . 05 ma , 1 μa to 00 . 4 ma , 1 μa to 0 . 03 ma , 1 μa to 0 . 02 ma , and 1 μa to 0 . 01 ma . in further certain aspects of the invention , the intensity range is between about 1 μa to 10 μa , 2 μa to 9 μa , 3 μa to 8 μa , 4 μa to 7 μa , and 5 μa to 6 μa . it is noted that certain aspects of stimulation ( e . g ., the mode , frequency , intensity , etc .) of the zi has been provided herein for illustration purposes and in no way limits the invention since at least one novel and non - obvious aspect of the invention is the elucidation of a causative effect of zi abnormalities and responses to pain , and the ability to modulate pain responses by stimulating the zi . electrical stimulation of the zi ( either directly or indirectly ) can be carried out , for example , with a subcranially implanted stimulating electrode or by a transcranial device or method ( including , for example , transcranial magnetic stimulation ). in certain aspects of the invention , a stimulating electrode may be placed within or directly adjacent to the zi to provide for the electrical stimulus of the zi that causes an increase in gabaergic neuron firing ( including , for example , gabaergic neurons projecting to the po ). in other aspects of the invention , a transcranial device or method can be used to achieve electrical or magnetic stimulation of the zi ( for both subcranially implanted stimulating electrodes and transcranial devices and methods see , for example , u . s . pat . no . 7 , 437 , 196 ; u . s . pat . no . 7 , 422 , 555 ; u . s . pat . no . 7 , 346 , 382 ; u . s . pat . no . 7 , 302 , 298 ; u . s . pat . no . 6 , 493 , 576 ; u . s . pat . no . 6 , 484 , 059 ; u . s . pat . no . 5 , 713 , 922 ; us patent application publication no . 20090030480 ; us patent application publication no . 20090024187 ; us patent application publication no . 20090024044 ; us patent application publication no . 20080312716 ; us patent application publication no . 20080294033 ; us patent application publication no . 20080269836 ; us patent application publication no . 20080214920 ; us patent application publication no . 20080208287 ; us patent application publication no . 20080208283 ; us patent application publication no . 20080154341 ; all of which are incorporated by reference in their entirety ). in certain aspects , the invention is drawn to the treatment of cps , which has no cure or effective treatment . in other aspects , the invention is drawn to the treatment of hyperalgesia or allodynia that is associated with cps and is not associated with cps . methods for treating hyperalgesia or allodynia are the same as those described for cps ( e . g ., direct or indirect electrical stimulation of the zi that causes an increase in gabaergic neuron firing ( including , for example , gabaergic neurons projecting to the po )). cps is a neurological condition caused by damage to or dysfunction of the central nervous system ( cns ), which includes the brain , brainstem , and / or spinal cord . cps can be caused by , for example , a stroke , multiple sclerosis , a tumor , epilepsy , brain or spinal cord trauma ( including , for example , traumatic brain injury ), or parkinson &# 39 ; s disease . the character of the pain associated with this syndrome differs widely among individuals partly because of the variety of potential causes . cps may affect a large portion of the body or may be more restricted to specific areas , such as hands or feet . pain is typically constant , may be moderate to severe in intensity , and is often made worse by touch , movement , emotions , and temperature changes , usually cold temperatures . individuals experience one or more types of pain sensations , the most prominent being burning . mingled with the burning may be sensations of “ pins and needles ;” pressing , lacerating , or aching pain ; and brief , intolerable bursts of sharp pain similar to the pain caused by a dental probe on an exposed nerve . individuals may have numbness in the areas affected by the pain . the burning and loss of touch sensations are usually most severe on the distant parts of the body , such as the feet or hands . cps often begins shortly after the causative injury or damage , but may be delayed by months or even years , especially if for example , it is related to post - stroke pain . in aspects of the invention drawn to spinal cord injury , the spinal cord injury results in injury to the stt , which can be transient or permanent . in particular aspects , injury to the stt is anywhere along the spinal column . in other particular aspects , injury to the stt is between vertebrae c6 and t9 . the inventors discovered that the zi plays an essential role in the pathophysiology of cps . consistent with this , the inventors found a significant suppression of both spontaneous and evoked activity in inhibitory neurons in the zi and abnormally high spontaneous and evoked activity of neurons in the po of animals with cps . furthermore , reduced hyperalgesia after electrical stimulation of the zi and the positive association between behavioral and neurophysiological thresholds in rats with cps is consistent with a causal role for suppressed incerto - thalamic inputs in cps . a role for the incerto - thalamic pathway in cps is also consistent with previous findings demonstrating that , in normal rats , the zi regulates both spontaneous and evoked activity of po neurons ( trageser and keller , 2004 ; trageser et al ., 2006 ) ( see also lavallee et al ., 2005 ). the inventors considered the possibility that there is a reduction in other inhibitory inputs to the po . there are no gabaergic interneurons within the po ( barbaresi et al ., 1986 ) and , therefore , all gabaergic inhibition is mediated by extrinsic afferents . an important source of these afferents is the gabaergic reticular nucleus of the thalamus ( trn ), which has been hypothesized to play a role in cps ( foix et al ., 1922 ; boivie , 2005 ). trn does not receive does not receive ascending sensory inputs , and its major source of excitatory input is from somatosensory cortex ( liu and jones , 1999 ). pharmacological suppression or lesions of the somatosensory cortex — which eliminate sensory responses in trn — fail to reveal short - latency responses in the po ( diamond et al ., 1992a ). therefore , gabaergic inhibition from trn is unlikely to be involved in directly regulating po responses . further , gabaergic terminals in the po that originate from the zi differ from those of trn origin by their larger size , the presence of multiple release sites , and multiple filamentous contacts , all features suggesting that the zi exerts significantly more potent inhibition upon the po ( bartho et al ., 2002 ; bokor et al ., 2005 ). moreover , the inventors demonstrated that responses evoked with innocuous stimuli in vpm and vpl — nuclei that receive inhibition exclusively from trn — were unaffected by spinal lesions , which argues against a role for trn in cps . the anterior pretectal nucleus ( apt ) also sends dense gabaergic inputs exclusively to higher - order thalamic nuclei , and it too can regulate the activity of po neurons ( bokor et al ., 2005 ). further , both the zi and apt receive dense nociceptive inputs through the stt ( apkarian and hodge , 1989 ; shaw and mitrofanis , 2001 ; craig , 2004 ), and both the zi and apt have been implicated in a variety of pain - related functions ( yen et al ., 1989 ; porro et al ., 2003 ; villarreal et al ., 2004 ; villarreal and prado , 2007 ). these findings suggest that apt might also be involved in the pathogenesis of cps . therefore , the inventors consider the zi and / or apt to be the most parsimonious candidates providing inhibitory regulation of the po . it is contemplated herein that apt , like that of zi , activity is suppressed in cps and that the instant invention also encompasses stimulating apt gabaergic projecting to the po . in addition to the po , the zi and apt innervate higher order thalamic nuclei that have been traditionally implicated in nociceptive processing , including the medial dorsal nucleus , the central median nucleus , nucleus submedius and the parafasicular nucleus ( craig and burton , 1981 ; bushnell and duncan , 1989 ; dostrovsky and guilbaud , 1990 ; power and mitrofanis , 2002 ). it is possible that neuronal activity in these nuclei is enhanced in animals with cps . together with the po , these nuclei project to cortical areas associated with the experience of pain ( reviewed in jones , 2007 ), and abnormalities in their neuronal activity — caused by reduced inhibition from the zi and / or apt — may play an integral part in the development or maintenance of cps . the invention described herein contemplates that the zi and / or apt play an integral role in cps and that stimulating either or both of these nuclei provides a novel method of treating cps and other pain related pathophysiologies . recordings of field potentials in brain slices taken from animals with cps after spinal lesions reveal that bursting discharges are evoked in vpl in response to local electrical stimulation ( wang and thompson , 2008a ). the absence of abnormal vpl responses in the present experiments might be explained by differences in the nature of the stimulus or by the urethane anesthetic . the zi also projects to the somatosensory cortex ( nicolelis et al ., 1995 ). zi projections upon the neocortex are sparse in adult animals , and they preferentially target cortical layer i ( dammerman et al ., 2000 ). thus , cortical influences upon the po are unlikely to be affected by suppression of zi input to the cortex . superior colliculus , and other structures inhibited by the zi and / or apt , provide relatively sparse inputs to the po , and are not thought to significantly shape its response properties ( ling et al ., 1997 ). it is possible that enhanced po responses in cps may be due to enhanced excitatory inputs , rather than or in addition to , reduced inhibition . the main sources of excitation to the po are the spinal trigeminal nuclei , the spinal dorsal horn , and the somatosensory cortex ( diamond et al ., 1992a ; pierret et al ., 2000 ; zhang and giesler , 2005 ). the inventors found that neuronal responses in spvi and spvc were not affected by spinal lesions and thus are unlikely to contribute to changes in the po . the inventors did not directly test the contribution of peripheral inputs from the dorsal horn or cortical inputs to the po , and thus their involvement in cps remains unknown . similarly , the contribution of “ modulatory ” inputs , such as cholinergic or serotonergic afferents , cannot be excluded ( varela and sherman , 2007 ). however , these spinal , cortical , and modulatory inputs also project upon the vpm and vpl nuclei , and evoked responses in these nuclei remain unchanged in animals with cps . therefore , the inventors conclude that disinhibition from the zi and / or apt upon the po and related nuclei is an important mechanism and target in the pathophysiology and treatment of cps . while the invention has been described with reference to certain particular aspects thereof , those skilled in the art will appreciate that various modifications may be made without departing from the spirit and scope of the invention . the scope of the appended claims is not to be limited to the specific aspects described herein . certain aspects of the invention have been carried out based on practices in the field of physiology and neurophysiology . some of these methods are described herein . others are known to those of ordinary skill in the art and have not been described herein , but are still considered for the purposes of , for example , enabling the invention . all procedures were conducted in accordance with animal welfare act regulations and phs guidelines . strict aseptic surgical procedures were used , in accordance with the guidelines of the international association for the study of pain , and were approved by the university of maryland school of medicine animal care and use committee . thirty - four adult female sprague - dawley rats weighing 250 - 300 g were used . animals were anesthetized with ketamine / xylazine ( 100 / 8 mg / kg ; i . p ), and the animals were placed on a thermo - regulated heating pad . a laminectomy to expose the spinal cord was performed and a quartz - insulated platinum electrode ( 5 μm tip ) was targeted to the stt , based on stereotaxic coordinates , on one side of the spinal cord . dc current ( 10 μa for 10 sec , repeated 4 times ) was passed through the electrode to produce an electrolytic lesion ( approximately 0 . 6 mm3 ). sham surgery was performed without performing laminectomy . the analgesic buprenorphine ( 0 . 05 mg / kg ) was administered every 12 hours for 24 hours post - operatively ( 2 doses total ). cold withdrawal thresholds . animals were tested for cold hyperalgesia at least 14 days after sham or lesion surgery . the animals were allowed to stand upright with the forepaws on the experimenter &# 39 ; s hand . a thermo - regulated cold copper probe ( 2 ° c ., 6 mm diameter ) was applied to the hind paw ipsilateral to the lesion site . an experimenter , blind to the treatment , applied the probe to the dorsal surface of the paw and measured the latency to withdrawal . in control experiments , the same probe was applied without cooling to test that the animals withdrew their paws due to the cold temperature rather than the tactile sensation of the probe . mann whitney u test ( mwu ) was used to compare pre - and post - lesion data . mechanical withdrawal thresholds . animals were tested on three consecutive days before the lesion surgery , at day 3 post - surgery , at day 7 post - surgery , and at weekly intervals thereafter . to minimize the animals ’ anxiety they were habituated for two weeks prior to behavioral testing , and were trained to stand upright with the forepaws on the experimenter &# 39 ; s hand . calibrated von frey filaments ( stoelting , ill .) were applied to the hindpaw or the vibrissae pad . the inventors applied the filaments to the dorsal surface of the paws based on studies demonstrating that the dorsal approach more reliably and consistently detects threshold changes ( ren , 1999 ). vibrissae pad stimuli were applied as described in ( ren , 1999 ). mechanical withdrawal threshold was defined as the force at which the animal withdrew to 3 of the 5 stimuli delivered . friedman test , followed by mwu test were used to compare pre - and post - lesion data . to determine the sample size , a power analysis was performed for all experiments using α = 0 . 05 and power = 0 . 85 . reversal of mechanical hyperalgesia . buprenorphine hydrochloride ( hospira inc ., il ) was administered ( i . p .) at three different concentrations ( 10 , 30 and 75 μg / kg ) to rats with behaviorally confirmed mechanical hyperalgesia at least 14 days after spinal surgery . twenty minutes after administration , mechanical withdrawal thresholds to von frey filaments were assessed at the hindpaws and the vibrissae pad , and compared to thresholds obtained before the administration of the drug . behavioral testing was also repeated 24 hr later to confirm that the effects of buprenorphine were reversible . in a separate set of animals ( n = 6 ) after spinal surgery , chronic bipolar quartz - insulated tungsten electrodes were implanted in the zi , contralateral to the spinal lesions . approximately 3 weeks after the spinal and implantation surgeries , the animals developed mechanical hyperalgesia and exhibited signs of cps as determined by the behavioral tests described above . the inventors then compared withdrawal thresholds to mechanical stimuli during periods of zi stimulation ( 25 ua , 50 hz , 300 μs square pulses for 20 min ), with periods without zi stimulation . in control experiments the animals were attached to the stimulator but no current was delivered . only one experiment was performed per day and in each animal , the experiment was repeated 5 times for each condition ( stimulation on or off ). the experimenter was blinded to the conditions of the stimulation . extracellular recording . at least 14 days after surgery , rats were anesthetized with urethane ( 1 . 5 g / kg , i . p .) and prepared for extracellular recordings , as previously described ( masri et al ., 2006 ; masri et al ., 2008 ). the inventors selected urethane as an anesthetic because it is the only anesthetic that has no , or negligible , effects on glutamatergic and gabaergic transmission , and therefore produces only minimal disruption , if any , of signal transmission in the neocortex ( sceniak and maciver , 2006 ). the inventors digitized waveforms ( 40 khz ) recorded from well - isolated units through a plexon ( dallas , tex .) data acquisition system , and sorted units off - line with plexon ′ s offline sorter , using dual thresholds and principal component analyses . the inventors generated auto - correlograms with neuroexplorer software ( littleton , mass .) to confirm that the inventors obtained recordings from single units . mechanical stimulation . the inventors recorded spontaneous activity and responses to a series of mechanical stimuli with forces that spanned the innocuous and noxious range ( 6 to 200 g ) using an electronic von frey anesthesiometer ( iitc inc ., ca ). forces were applied to the dorsal hindpaw or the face , ipsilateral to the lesion site 10 times each in a randomized order . the inventors computed mean firing rate during spontaneous activity periods and during application of each level of mechanical stimulation . the inventors used repeated measures anova followed by dunnett &# 39 ; s post hoc test to determine the lowest mechanical force that produced neuronal firing that differed significantly ( p & lt ; 0 . 05 ) from spontaneous activity . vibrissae stimulation . the inventors stimulated vibrissae ipsilateral to the lesion site with air puffs delivered through a tube , as in our previous studies ( magi et al ., 2008 ). the inventors exported time stamps of well - isolated units and of stimulus triggers to matlab ( mathworks , natick , mass .) for analyses using custom - written algorithms . the inventors constructed peristimulus time histograms ( psths , 1 ms bins ), and defined significant stimulus - evoked responses as psth bins whose response magnitude significantly exceeded ( 99 % confidence interval ) spontaneous activity levels , computed from a 200 ms period preceding the stimuli . the inventors performed statistical analyses in stata ( statacorp lp ., tx ), and assessed , in individual neurons , changes occurring in sensory - evoked activity using the mwu test ; p & lt ; 0 . 05 was considered significant . burst analysis . the inventors identified bursts of action potentials as clusters of at least three spikes with interspike intervals of ≦ 4 ms , in which the first spike in the burst has a preceding interspike interval of at least 100 ms ( lu et al ., 1992 ; guido et al ., 1995 ; sherman , 1996 ). identification of recording , stimulation and spinal lesion sites . the inventors marked recording sites by placing electrolytic lesions ( 5 μa for 10 sec ) at the end of each experiment , then deeply anesthetized the rats and perfused them transcardially with buffered saline followed by 4 % buffered paraformaldehyde . the inventors obtained coronal brain and spinal sections ( 70 μm thick ) and nissl - stained the sections to identify recording and lesion sites . the inventors and others have previously shown that cps develops in rats following lesions of the spinal cord ( siddall et al ., 1995 ; mills et al ., 2001 ; endo et al ., 2008 ; wang and thompson , 2008b ). because the spinothalamocortical system is affected in all central pain patients , the inventors experimentally produced lesions that included the spinothalamic tract ( stt ). rats ( n = 18 ) received a single , unilateral electrolytic lesion in the anterolateral quadrant of the spinal cord , at lower cervical to upper thoracic levels ( fig1 a ). in rats , stt afferents to medial and lateral thalamic nuclei travel in the ventral and ventrolateral funiculi of the spinal cord ( giesler et al ., 1981 ). the inventors therefore targeted lesions to these spinal cord regions ( fig1 b ). in spinal - lesioned animals — and in contrast to animals receiving sham surgery — hindpaw withdrawal thresholds to mechanical stimulation of the dorsal paw surface transiently increased ( hypoalgesia ) immediately after the lesion . subsequently , significant reductions in thresholds ( hyperalgesia ) were evident bilaterally by 14 days post - lesion ( fig2 a ). mechanical thresholds decreased from 84 ± 22 g to 47 ± 21 g ( p = 0 . 007 , friedman ) on the ipsilateral hindpaw and from 86 ± 29 g to 44 ± 17 g ( p = 0 . 007 ) on the contralateral hindpaw . the reduction in withdrawal threshold was evident in 94 % of spinal - lesioned animals and persisted for the duration of the experiments ( up to 42 days ; fig2 a ). stimulus - response curves constructed from results obtained 14 days after surgery demonstrate a leftward shift in mechanical thresholds after spinal lesion ( fig2 b ). the transient hypoalgesia seen immediately after lesion surgery , followed by bilateral hyperalgesia , is consistent with findings in human patients suffering from cps following spinal injury ( bowsher , 1995 ; finnerup et al ., 2003 ; boivie , 2005 ). the inventors also tested responses to cold stimuli because these stimuli reliably and selectively activate nociceptors , and because cold hyperalgesia is a common complaint of cps patients ( defrin et al ., 2002b ; finnerup et al ., 2003 ). animals with spinal lesions ( n = 14 ) were more sensitive to cold stimuli ( cold hyperalgesia ) applied to the dorsal surface of the ipsilateral hindpaw , compared to sham operated control animals ( n = 12 ); paw withdrawal latencies were 4 . 8 ± 2 . 8 sec in sham - operate , and 1 . 7 ± 1 . 1 sec in animals with spinal lesions ( p = 0 . 001 , mwu ; fig2 c ). histological analyses revealed that lesions at any level between c6 and t9 produced similar cps - like behavioral effects , consistent with findings in humans that cps can result from lesions anywhere along the spinothalamocortical pathway ( see above ). as with lesions in cps patients , our experimental lesions are unlikely to completely ablate or selectively involve the stt . rather , as in humans , the inventors find that lesions that involve the stt result in cps . a summary of the location and size of all lesion sites is shown in fig1 b . in all animals with behaviorally confirmed cps , the lesions affected parts of the stt . to confirm that withdrawal from mechanical stimuli reflects a response to painful stimuli , the inventors administered buprenorphine — a centrally acting opiate — to 4 animals with confirmed hyperalgesia . this resulted in a dose - dependent reversal in the reduction of hindpaw withdrawal thresholds ( fig2 d ). the effects of buprenorphine were reversible and withdrawal thresholds returned to pre - administration levels at subsequent tests . thus , as in humans with cps , centrally acting opiates can acutely reverse hyperalgesia , although opiates offer no long - term benefit to these patients ( eide et al ., 1995 ; attal et al ., 2002 ). signs of central pain were not limited to the hindpaws , as hyperalgesia extended to include the face . fig2 e shows that mechanical thresholds for face withdrawal began to decrease 3 days after surgery and were significantly lower than pre - lesion values at 21 days post - lesion ( ipsilateral : 29 ± 18 g , median = 26 g , p = 0 . 007 , friedman ; contralateral : 25 ± 15 g , median 26 g , p = 0 . 007 , friedman ). similar to its effects on hindpaw hyperalgesia , buprenorphine reversed the reduction in face withdrawal thresholds in spinal - lesioned animals in a dose - dependent , reversible manner ( fig2 f ). consistent with previous reports in experimental animals with cps ( stormer et al ., 1997 ; yezierski , 2000 ; defrin et al ., 2002a ), these findings demonstrate that animals with spinal lesions present with diffuse , bilateral mechanical hyperalgesia that involves dermatomes below and above the lesion site . furthermore , spinal - lesioned animals are significantly hyperalgesic to cold stimuli ipsilateral to the lesion site . therefore , this model of central pain recapitulates clinical characteristics of cps , as described above , and allowed for directly elucidating and testing mechanisms responsible for cps . the zona incerta ( zi ) is aptly named : the function of this “ zone of uncertainty ”, situated ventral to the thalamus , has been debated since auguste forel first described it in 1877 ( forel , 1877 ). zi receives dense nociceptive inputs through the stt ( shammah - lagnado et al ., 1985 ; craig , 2004 ), and has been implicated in a variety of functions ( yen et al ., 1989 ; pono et al ., 2003 ). a striking feature of the zi is its target specificity ( bartho et al , 2002 ; mitrofanis , 2005 ). in all sensory systems it provides inhibitory inputs exclusively to “ higher order ” thalamic nuclei ( e . g ., posterior nucleus in the somatosensory system and the inferior pulvinar in the visual system ). zi afferents avoid first - order thalamic nuclei ( e . g ., ventroposterior in the somatosensory system and the lateral geniculate in the visual system ). zi sends a dense gabaergic projection upon the posterior nucleus of the thalamus ( po ) ( power et al ., 1999 ; bartho et al ., 2002 ), a nucleus critically involved in nociceptive processing ( poggio and mountcastle , 1960 ; casey , 1966 ; apkarian and shi , 1994 ; zhang and giesler , 2005 ). the inventors recently showed that the zi exerts potent feed - forward and tonic inhibition of po neurons ( trageser and keller , 2004 ; trageser et al ., 2006 ), ( also see lavallee et al ., 2005 ). because of these properties of the zi the inventors hypothesized that responses or activity in the zi are affected in cps . to test this , the inventors recorded spontaneous and stimulus - invoked activity from well - isolated neurons in the ventro - lateral sector of the zi ( n = 17 from spinal - lesioned rats and n = 18 from sham - operated controls ). the inventors have recently shown that essentially all cells in this sector are inhibitory neurons that project to the po ( trageser et al ., 2006 ). the inventors tested responses of zi neurons to stimulation of the mystacial vibrissae — the whiskers on rats &# 39 ; face — because of the large somatotopic representation of the vibrissae in the zi ( nicolelis et al ., 1992 ), because of the reliability in which controlled stimuli can be applied , and because of the presence of lesion - induced hyperalgesia in the vibrissae pad . fig3 a compares activity recorded from a zi neuron in a sham - operated rat ( control ) with activity recorded from a rat with a spinal lesion and behaviorally confirmed hyperalgesia . in the neuron recorded from the spinal - lesioned rat the spontaneous firing rate ( 1 . 6 hz ) is noticeably lower than in the neuron from the sham - operated rat ( 12 hz ). the magnitude of the vibrissae - evoked response in the spinal - lesioned rat ( 0 . 04 spikes / stimulus ) is also markedly lower than in the sham - operated control ( 1 . 5 spikes / stimulus ). as a group , zi neurons from spinal - lesioned rats have significantly lower spontaneous firing rates ( 0 . 29 ± 0 . 28 hz vs . 0 . 80 ± 0 . 70 hz in shams , p = 0 . 006 , fig3 b ), and lower vibrissae - evoked responses ( 1 . 0 ± 0 . 7 spikes / stimulus vs . 1 . 4 ± 1 . 3 spikes / stimulus in shams , p = 0 . 04 , fig3 c ). to determine if suppressed activity in the zi is causally responsible for mechanical hyperalgesia in animals with cps , the inventors stimulated the zi using chronically implanted stimulation electrodes . fig3 d details the effect of electrical stimulation on mechanical withdrawal thresholds ( n = 6 rats ). when the inventors applied mechanical stimuli while stimulating the zi , withdrawal thresholds were significantly increased , and typically returned to pre - lesion levels . zi stimulation reversed mechanical hyperalgesia in one or both of the hindpaws ( range : 0 - 80 % increase in threshold of hindpaw ipsilateral to the lesion , 25 - 93 % increase contralaterally ; p & lt ; 0 . 05 , mwu ; fig3 d ). because the zi normally exerts potent tonic and feed - forward inhibition upon the po ( see above ), the inventors postulated that suppressed zi activity would result in abnormally high activity in the po . to test this , the inventors recorded spontaneous and stimulus - evoked responses from po neurons of spina - lesioned rats with confirmed cps , and from sham - operated controls . recording from a representative po neuron from an animal with cps are shown in fig4 a . the inventors applied mechanical stimuli to the dorsal surface of the hindpaw , ipsilateral to the lesion site , with the use of an electronic anesthesiometer ; force traces are shown at the bottom . note that this neuron responds with a larger number of spikes to increasing mechanical forces . the relationship between stimulus intensity and firing rate is shown in fig4 b for po neurons from a sham - operated rat (“ control ”) and from a spinal - lesioned rat with confirmed cps (“ cps ”). the control po neuron fired spontaneously at low rates that were not significantly modulated by mechanical stimuli until the force applied exceeded 180 g ( p = 0 . 019 , anova ); this force was identical to the one required to evoke a withdrawal response from the same animal during behavioral test sessions . in contrast , the po neuron recorded from the rat with cps exhibited significantly higher spontaneous activity , and responded to increasing mechanical forces with increasing firing rates . the threshold for significant responses ( 60 g , p & lt ; 0 . 0001 ) corresponded to the behavioral withdrawal threshold , and both behavioral and electrophysiological thresholds were markedly lower than in the control animal . stimulus - response curves constructed from neuronal responses to mechanical stimuli show a significant leftward shift for spinal - lesioned animals compared to shams , consistent with the leftward shift observed for the behavioral responses ( sham threshold = 180 g ; cps threshold = 60 g , fig4 c ). as a group , spontaneous activity in po neurons of animals with cps was approximately 30 - fold higher than in sham - operated animals ( sham : mean = 0 . 37 ± 0 . 40 , median = 0 . 2 hz , n = 12 ; cps : mean = 10 . 7 ± 16 . 6 hz , median = 5 . 6 hz , n = 15 ; p & lt ; 0 . 0001 , mwu , fig4 e ). in all cases , the force required to elicit a significant change from baseline ( spontaneous ) neuronal firing correlated with the force needed to elicit paw withdrawal in both sham - operated and spinal - lesioned animals . to determine if behavioral hyperalgesia in the face is also reflected in abnormal po activity , the inventors recorded , in the same set of neurons , responses to stimulation of the vibrissae . peristimulus histograms ( psth ) were constructed for each cell to compute response magnitude . typical of po neurons in control animals ( diamond et al ., 1992b ; trageser and keller , 2004 ; lavallee et al ., 2005 ), the unit depicted in fig4 d (“ control ”) exhibited low spontaneous activity and low - magnitude responses to vibrissae stimuli . in contrast , the unit recorded from an animal with cps responded robustly to vibrissae stimuli and had a markedly high spontaneous firing rate (“ cps ”). as a group , evoked response magnitudes of po neurons from spinal - lesioned animals were significantly higher than those of control animals ( sham : mean = 0 . 86 ± 0 . 39 spikes / stimulus , median = 0 . 60 spikes / stimulus ; cps : mean = 3 . 2 ± 5 . 6 , median = 1 . 2 spikes / stimulus , p = 0 . 008 , mwu , fig4 f ). taken together , these results demonstrate that spinal lesions produce abnormally high spontaneous firing and enhanced po responses to stimuli from dermatomes both below and above the lesion site . the finding that thresholds for po responses decrease in parallel with hindpaw withdrawal thresholds demonstrate that the two phenomena are causally related , and that changes in po responses support behavioral responses to hyperalgesia . as described herein , the zi specifically targets “ higher order ” thalamic nuclei , while avoiding “ first order ” thalamic nuclei such as the somatosensory ventral posteromedial thalamus ( vpm ) and the ventral posterolateral thalamus ( vpl ) ( bartho et al ., 2002 ). because vpm and vpl activity is not regulated by zi inputs the inventors predicted that activity in these nuclei would not be affected in animals with cps . to investigate this prediction the inventors first recorded from vpl neurons that respond to hindpaw stimulation ( n = 12 each from spinal - lesioned rats and sham - operated controls ). there was no significant difference in the magnitude of responses evoked by innocuous ( 50 gram ) mechanical stimulation ( sham : 1 . 70 ± 1 . 39 hz ; cps : 1 . 79 ± 1 . 32 hz ; p = 0 . 9 , mwu , fig5 a ) or noxious ( 120 gram ) stimulation ( sham : 2 . 28 ± 0 . 43 hz ; cps : 2 . 87 ± 1 . 31 hz ; p = 0 . 5 ). there was also no difference between spontaneous firing rates of neurons recorded from spinal - lesioned animals and those of sham - operated controls ( sham : 0 . 28 ± 0 . 35 hz ; cps : 0 . 26 ± 0 . 26 hz ; p = 0 . 9 mwu , fig5 a ). the finding that activity in vpl neurons was unaffected in cps is consistent with the model that suppressed inhibitory inputs from the zi to the po is causally related to cps . the inventors also recorded from vpm neurons that respond to innocuous vibrissae stimulation ( n = 10 from spinal - lesioned rats and n = 13 from sham - operated controls ). consistent with our prediction , group comparisons revealed no significant difference in the magnitude of evoked responses in vpm ( sham : 1 . 4 ± 2 . 0 spikes / stimulus ; cps : 1 . 1 ± 1 . 3 spikes / stimulus ; p = 0 . 8 , mwu , fig5 b ). there was , however , a modest increase in spontaneous firing rates in neurons recorded from spinal - lesioned animals ( sham : 1 . 4 ± 2 . 2 hz ; cps : 6 . 2 ± 7 . 5 hz ; p = 0 . 04 , mwu , fig5 c ) ( compare the 30 - fold increase in spontaneous activity of po neurons with the 4 - fold increase in vpm ). the finding that evoked activity in vpm neurons was unaffected in cps is consistent with the model wherein abnormalities in the zi are responsible for the development of cps . it has been suggested previously that cps , in both humans and animal models , is associated with abnormally high incidence of bursting activity in lemniscal thalamic nuclei ( lenz et al ., 1989 ; vierck et al ., 1990 ; weng et al ., 2003 ; lee et al ., 2005 ; but see also dostrovsky , 2007 ). the inventors therefore reasoned that the increased spontaneous activity in vpm might be due to an increase in the incidence of burst firing in this nucleus , as proposed previously for vpl ( wang and thompson , 2008b ). to test this prediction the inventors analyzed the incidence of bursts during spontaneous activity and in response to vibrissae stimuli . in spinal - lesioned rats there was a large and significant increase ( p = 0 . 02 , χ2 test ) in the percentage of vpm neurons that emitted bursts of 3 or more action potentials ( sham : 23 %; cps : 70 %). however , in bursting cells , the mean frequency of bursts was only marginally , and not significantly ( p = 0 . 06 , mwu ), higher in spinal - lesioned rats ( sham : mean = 0 . 02 ± 0 . 05 hz , median = 0 hz , cps : mean = 0 . 04 ± 0 . 05 hz , median = 0 . 02 hz . vpm neurons that respond with bursts to vibrissae stimulation was not significantly different between the two groups ( sham : 44 %, cps : 38 %; p = 0 . 44 , χ2 test ). nor was there a difference in the frequency of stimulus - evoked bursts between sham - operated and spinal - lesioned animals ( sham : mean = 0 . 01 ± 0 . 03 hz , median = 0 hz ; cps : mean = 0 . 03 ± 0 . 06 hz , median = 0 . 002 hz , p = 0 . 5 , mwu ). the inventors performed similar analyses of spike bursts on po neurons , and found no significant difference in either the percentage of spontaneously bursting cells ( sham : 50 %; cps : 47 %; p = 0 . 90 , χ2 test ), or in the frequency of spontaneous bursts ( sham : mean = 0 . 04 ± 0 . 08 hz , median = 0 . 002 hz ; cps : mean = 0 . 04 ± 0 . 06 hz , median = 0 hz , p = 0 . 80 , mwu ). similarly , neither the percentage of cells that burst in response to vibrissae stimuli ( sham : 40 %; cps : 53 %; p = 0 . 30 , χ2 test ), nor the incidence of evoked bursts ( sham : mean = 0 . 02 ± 0 . 04 hz , median = 0 hz ; cps : mean = 0 . 02 ± 0 . 04 hz , median = 0 . 004 hz , p = 0 . 5 , mwu ), are significantly different in rats with cps . these findings indicate that the incidence of spike bursts — as defined in this study — are only marginally affected in vpm neurons , and remain unchanged in vpl and po neurons . the changes in activity of po neurons in cps animals may reflect an increase in peripheral afferent input , rather than — or in addition to — a reduction in inhibition from the zi . to further investigate this , the inventors recorded activity from the spinal trigeminal nucleus ( spv ), the main source of afferent inputs to the po ( veinante et al ., 2000 ). spontaneous firing rates of vibrissae responsive neurons in the spinal trigeminal subnucleus interpolaris ( spvi ) were not significantly different between neurons recorded from sham - operated and spinal - lesioned animals ( sham : mean = 0 . 68 ± 1 . 8 hz , median = 0 . 17 hz , n = 11 ; cps : mean = 0 . 99 ± 2 . 1 hz , median = 0 hz , n = 10 ; p = 0 . 96 , mwu , fig5 d ). there was also no significant difference in the magnitude of response to vibrissae stimuli ( sham : mean = 2 . 27 ± 2 . 07 spikes / stimulus , median = 1 . 47 spikes / stimulus ; cps : mean = 2 . 03 ± 1 . 18 spikes / stimulus , median = 1 . 65 spikes / stimulus ; p = 0 . 82 , mwu , fig5 e ). to investigate if &# 39 ; changes in the po reflect peripheral changes in nociceptive afferents from the face , the inventors recorded from neurons in the spinal trigeminal subnucleus caudalis ( spvc ). spontaneous firing rates of neurons in spvc of spinal - lesioned animals were not significantly different from neurons recorded from sham - operated controls ( sham : mean = 1 . 8 ± 2 . 5 hz , n = 12 ; cps : mean = 2 . 3 ± 5 . 0 hz , n = 13 ; p = 0 . 65 , mwu , fig5 f ). in addition , responses of these neurons to noxious mechanical stimuli applied to the face were not significantly different between the two groups ( sham : mean = 10 . 4 ± 7 . 2 spikes / stimulus ; cps : mean = 10 . 5 ± 11 . 3 spikes / stimulus ; p = 0 . 53 , mwu , fig5 f ). these findings indicate that changes in po activity in spinal - lesioned rats are not due to increased afferent inputs from spvi or spvc . all patents and publications mentioned in this specification are indicative of the level of those skilled in the art to which the invention pertains . all patents and publications herein are incorporated by reference to the same extent as if each individual publication was specifically and individually indicated as having been incorporated by reference in its entirety . all of the following references have been cited in this application : apkarian , a v , hodge , c j ( 1989 ) primate spinothalamic pathways : iii . thalamic terminations of the dorsolateral and ventral spinothalamic pathways . j comp neurol , 288 : 493 - 511 . apkarian , a v , shi , t ( 1994 ) squirrel 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