Anesthetics are used extensively clinically and in research. However, the mechanisms by which anesthetics act to produce the desired end-points of unconsciousness, amnesia and immobility are only beginning to be understood. Recent evidence indicates that the immobilizing effect of anesthetics occurs largely in the spinal cord, whereas it is assumed that the sedative and amnesic actions occur in the brain. Our recent studies, however, indicate that anesthetics exert an indirect, spinal effect on reticulo-thalamo-cortical mechanisms of arousal and, thus, might affect consciousness and memory. These data are consistent with reports of reduced anesthetic requirements for sedation during neuroaxial blockade by spinal anesthesia. The presumed mechanism is decreased afferent impulses to the brain, which reduces arousal and, thereby, reduces sedative requirements. We have used the complementary approaches of single-unit recording and intracranial electrical stimulation to investigate the effects of a common inhaled anesthetic, isoflurane, on reticulo-thalamo-cortical arousal in a goat preparation. The excitatory responses of single neurons in the midbrain reticular formation (MRF) to noxious somatic stimulation are significantly attenuated when the concentration of systemically delivered isoflurane was increased above 1 MAC (the minimum alveolar concentration required to prevent coordinated movement in response to a noxious stimulus), in parallel with a loss of stimulus-evoked desynchronization of the cortical electroencephalogram (EEG). Part of this depressant effect is mediated indirectly in the spinal cord because selectively reducing the concentration of isoflurane delivered differentially to the spinal cord enhances MRF neuronal responses and cortical arousal. In goats anesthetized with isoflurane at ∼1 MAC, electrical stimulation at distinct sites, including the MRF, peduncolopontine tegmentum (PTT), and medial/intralaminar thalamus, elicits desynchronization of the cortical EEG. Increasing the concentration of isoflurane above 1 MAC abolished this effect. In goats prepared for differential delivery of anesthetic to the cranial and torso (spinal) circulations, electrical stimulation in the medial thalamus elicits greater cortical desynchronization at lower currents when the concentration of isoflurane delivered to the spinal cord is reduced while maintaining the cranial isoflurane concentration ≥1 MAC. These results indicate that the depressant effect of isoflurane anesthesia on spinal somatosensory transmission indirectly influences the threshold for reticulo-thalamo-cortical arousal.

Previous studies have demonstrated that peripheral inflammation leads to long-term increases in spinal dorsal horn neuronal excitability (i.e. central sensitization) and behavioral hyperalgesia that is mediated by glutamate receptor activation. The present study has examined spinal cord changes in serine phosphorylation of the NMDA receptor NR1 and AMPA receptor GluR1 subunits after peripheral inflammation. Using site-specific antibodies, Western blots showed a significant increase in phosphorylation at serine residues 896 and 897 of the NR1 and at serine residues 831 and 845 of the GluR1 subunits in the rat spinal cord after injection of complete Freund's adjuvant into the hindpaw. For all four serine sites, the increased phosphoserine NR1 and GluR1 levels occurred as early as 10 minutes, lasted for at least 3 days, and returned to control level 7–14 days following inflammation. There was also an increase in total NR1 and GluR1 proteins after inflammation, but with a different time course. The phosphorylation of different serine residues of NR1 and GluR1 depended on input from the injured site. Local anesthesia of the inflamed paw with lidocaine (2%), blocked the increase in phosphoserine 896 (NR1) and phosphoserine 831 (GluR1) with a time course corresponding to the duration of anesthesia. However, the increased phosphoserine 845 (GluR1) was blocked only transiently and the concentration of phosphoserine 897 (NR1) was not affected by local anesthesia. Consistent with previous biochemical analysis, phosphorylation of serine 896 NR1 and serine 831 of GluR1 was blocked by intrathecal chelerythrine (0.01–1 nmol), a PKC inhibitor, and phosphorylation of serine 897 NR1 was blocked by H-89 (0.01–1 nmol), a PKA inhibitor. In addition, there appeared to be an interaction between the PKC and PKA cellular pathways because phosphorylation of serine 897 of NR1, a substrate of PKA, was also blocked by chelerythrine. These findings correlate serine phosphorylation of the NR1 and GluR1 subunits to spinal hyperexcitability and hyperalgesia, and indicate a role of serine phosphorylation of NMDA and AMPA receptors in initiating central sensitization.

Activation of cyclic AMP response element-binding protein (CREB) in the spinal dorsal horn may be a crucial contributor to the activity-dependent synaptic plasticity that is thought to underlie the development of persistent pain following peripheral nerve injury. In this study, we examined the early period of CREB activation following chronic constriction injury (loose ligation) of the sciatic nerve in rats. The estimated levels of Ser133-phosphorylated (activated) CREB significantly increased at 2 hours (424 ± 85%) and remained elevated at 4 hours (349 ± 97%) and 8 hours (258 ± 69%) after sciatic ligation compared with control animals. By contrast, activated CREB levels in sham-operated animals were not significantly greater than in control animals except at 1 hour (176 ± 6%) and 8 hours (288 ± 16%). The maximal ligation-associated activation of CREB at 2 hours occurred bilaterally and was dependent, at least partly, on NMDA-receptor activation because pretreatment with 20 µg MK-801 significantly attenuated the ligation-associated activation of CREB. The levels of non-phosphorylated CREB in ligated and sham-operated animals did not differ significantly from controls at the time-points examined.

These data establish a significant, persistent increase in CREB phosphorylation within hours of loose ligation of the sciatic nerve and indicate an early but consequential injury-related shift in the manner in which spinal dorsal horn neurons processed sensory information. The data lend further support to the notion that ligation-associated CREB-dependent synaptic plasticity in the spinal dorsal horn might underlie the development of persistent pain following peripheral nerve injury.

Visceral nociceptive responses to distention of the ureter, and responses to innocuous and noxious mechanical stimulation of the skin were recorded from neurons in the ventral posterior lateral nucleus of the thalamus in anesthetized rats. The ventral posterior lateral (VPL) neurons were classified by their responses to cutaneous stimuli as either low-threshold or wide-dynamic-range neurons. No high-threshold neurons were found in the population of VPL neurons sampled. Some VPL neurons that responded to distention of the ureter appeared to lack a cutaneous receptive field. The majority of VPL neurons that responded to noxious visceral stimulation of the ureter were classified as low-threshold neurons, based on their responses to cutaneous stimuli. Transection of the DC at an upper cervical level dramatically reduced the responses of VPL neurons to ureter distention and to innocuous mechanical stimulation of the skin, but the responses to noxious mechanical stimulation of the skin remained intact. Ureter distention and mechanical stimulation of the skin might activate dorsal horn neurons, including postsynaptic dorsal-column pathway (PSDC) neurons and spinothalamic tract (STT) cells. We conclude that both the DC pathway and the STT are likely to contribute to the visceral and somatic responses of some VPL neurons.

Abnormal thalamocortical dynamics have been proposed as the underlying mechanism for a subset of neurological and psychiatric disorders that include centrally generated pain. Spectral analysis and independent component-based localization of neuromagnetic signals reveal ongoing theta-range activity localized to physiologically significant cortical regions in a group of subjects with well-characterized central and peripheral lesions. In addition, recordings from subjects who failed to obtain relief from spinal cord stimulation (SCS) and from those in whom SCS was successful further delineate thalamocortical dysrhythmias as a mechanism that underlies chronic pain.

The somatotopic organization, mechanoreceptive field (RF) and response properties of nociceptive neurons in the ventral posteromedial thalamic nucleus (VPM) were studied in urethane/α-chloralose anesthetized rats. Microelectrode recordings were made of the activity of single neurons within VPM, and neurons were identified as either nociceptive [wide-dynamic-range (WDR), nociceptive-specific (NS)] or non-nociceptive [low-threshold mechanoreceptive (LTM)]. Of the 350 neurons tested, 317 responded to orofacial mechanical stimulation; all the RFs were contralateral. The incidence of NS neurons was significantly higher than that of WDR neurons (21.2% versus 4.2%) but LTM neurons were most common (62.9%). WDR and NS neurons were scattered among the LTM neurons in the VPM. NS neurons were significantly denser in rostral and caudal portions of VPM; most of the WDR neurons (87%) were located in the core of VPM. Neurons with an ophthalmic division RF were located most dorsally and those with a mandibular division RF most ventrally. The RF of most neurons (77%) was located in the maxillary region, with the RF of nociceptive neurons mainly in the intraoral region and that of most LTM neurons in the perioral region. The majority of LTM, WDR and NS neurons tested had a low spontaneous activity and there was a significant difference in spontaneous firing between WDR and NS neurons, and between WDR and LTM neurons. The mean mechanical activation threshold of NS neurons (195 ± 11.2 g) was significantly higher than that of WDR neurons (4.7 ± 1.3 g). Response magnitude and peak firing frequency to graded mechanical stimuli were significantly higher in the WDR neurons. These findings indicate significant differences in the spontaneous activity, RF and response properties between WDR and NS neurons in VPM. However, they also indicate that both types of nociceptive neurons can encode the spatial properties and intensity of a noxious orofacial stimulus and, thus, might contribute to the sensory-discriminative component of pain.

Spindle oscillation is generated in intrathalamic circuits and thalamic reticular (RE) neurons act as pacemakers. To assess the consequences of this oscillation on membrane properties of RE neurons, we performed in vivo intracellular recordings in anesthetized cats during periods of intense synaptic activity, represented by spindle waves, compared to silent periods (interspindle lulls) that corresponded to a hyperpolarization of about −75 mV. During spindles, the massive activation of T-currents generated powerful low-threshold spikes (LTSs) that changed the membrane potential of RE cells by 10–20 mV and increased their membrane fluctuations by one order of magnitude (from 1–3 mV to 10 mV). Besides, the generation of LTSs decreased the apparent input resistance by ∼80% for ∼20–30 mseconds, in a cyclic way. The changes in basic membrane properties proved to be functionally significant for RE neurons, because both synaptic and intrinsic responsiveness were enhanced during active network states. Thus, synaptic responses tested by stimulating afferent (corticothalamic and thalamo-RE) pathways displayed increased spiking. The same result was found for intrinsic responses using positive and negative current pulses, and sinusoidal wave currents. Bursting discharges, responsible for the generation of the above changes, proved to be a very robust and reliable firing pattern in RE neurons. Our data demonstrate that ongoing network activity of RE neurons during spindle oscillations influence the expression of intrinsic properties of these pacemaking neurons, similarly to the previously shown effect exerted by spontaneously occurring synaptic activity on the intrinsic properties of thalamocortical and neocortical neurons.

Neurophysiological studies at the cellular level (microelectrode unit activity recordings and local field potentials) as well as electro- and magnetoencephalographic recordings provide converging evidence for a thalamocortical dysregulation at the source of chronic neurogenic pain of both peripheral and central origin. These indicate an increase of low frequency thalamocortical rhythmicity originating in disfacilitation of thalamic relay neurons, followed by cortical activation due to asymmetries of corticocortical inhibition. This process, called thalamocortical dysrhythmia, might become self-sustained and, thus, chronic due to recurrent thalamoreticulothalamic and corticoreticulothalamic feedback inhibition. Our surgical approach is centered on re-establishment of normal thalamocortical oscillatory activity using small, strategically placed medial thalamic and prethalamic lesions. These reduce the increased low frequency thalamocortical recurrent network activity via low frequency desamplification and thalamic disinhibition, providing long term therapeutic efficiency coupled with sparing of the specific thalamocortical loops.

This physiopathological framework should be helpful when considering differential mechanisms and treatment modalities for different types of chronic pain. It underscores the risks of any surgical procedure aiming at reducing further the activation of specific thalamic relay cells and, thus, increasing thalamic disfacilitation and dysrhythmic pain mechanisms. In addition, the normal low frequency generation by activation of the paralimbic and high order association networks provides, in the context of a well established thalamocorticothalamic divergent and, thus, interactive organization, a basis for understanding the relevance of the conceptual-affective internal environment in the maintenance and amplification of many chronic neurogenic pain situations.

Chronic pain is an immense, unsolved, clinical problem. Current approaches to this condition are limited by uncertainty about mechanisms of acute and chronic pain in humans. Although much progress has been made toward understanding peripheral neural mechanisms of human nociception, we have a poor understanding of CNS pain mechanisms. Here, we review the anatomy and physiology of the ascending spinal pathways and supraspinal centers with pain-related activity. This review focuses on the primate nervous systems because there are significant differences between pain transmission in primates and other species such as cats and rats.