Stimulation-produced Analgesia Research Articles

Alterations in the rostral ventromedial medulla after the selective ablation of μ-opioid receptor expressing neurons

The rostral ventromedial medulla (RVM) exerts both inhibitory and excitatory controls over nociceptive neurons in the spinal cord and medullary dorsal horn. Selective ablation of mu-opioid receptor (MOR)-expressing neurons in the RVM using saporin conjugated to the MOR agonist dermorphin-saporin (derm-sap) attenuates stress and injury-induced behavioral hypersensitivity, yet the effect of RVM derm-sap on the functional integrity of the descending inhibitory system and the properties of RVM neurons remain unknown. Three classes of RVM neurons (on-cells, off-cells, and neutral cells) have been described with distinct responses to noxious stimuli and MOR agonists. Using single unit recording in lightly anesthetized rats, RVM neurons were characterized after microinjections of derm-sap or saporin. Derm-sap treatment resulted in a reduction in on-cells and off-cells when compared to saporin controls (P < 0.05). The number of neutral cells remained unchanged. After derm-sap treatment, RVM microinjections of the glutamate receptor agonist homocysteic acid increased tail-flick latencies, whereas the MOR agonist DAMGO had no effect. Furthermore, electrical stimulation of the periaqueductal gray produced analgesia in both derm-sap and saporin controls with similar thresholds. Microinjection of kynurenic acid, a glutamate receptor antagonist, into the RVM disrupted periaqueductal gray stimulation-produced analgesia in both saporin-treated and derm-sap-treated rats. These results indicate that MOR-expressing neurons in the RVM are not required for analgesia produced by either direct or indirect activation of neurons in the RVM.

Antagonism of stimulation-produced analgesia by naloxone and N-methyl-D-aspartate: role of opioid and N-methyl-D-aspartate receptors

The present study aims to investigate the influence of electrical stimulation of periaqueductal gray (PAG) following peripheral nerve injury and its modulation by naloxone and N-methyl-D-aspartate (NMDA). Chronic neuropathic pain was induced by chronic constriction injury of the sciatic nerve, and subsequently a cannula was implanted in the PAG area for the purpose of electrical stimulation and intra-PAG drug administration. Intra-PAG administration of morphine, ketamine, and their combination were found to elicit antinociceptive response on hot-plate test. Electrical stimulation of PAG was also observed to demonstrate decreased pain response on hot-plate test, and this effect was reversed by the administration of naloxone, NMDA, and their combination, when injected into the PAG area. These findings suggest that apart from the opioid receptors, probably NMDA receptors also have a role to play in stimulation-produced analgesia.

Stimulation-Produced Analgesia From the Occipital or Retrosplenial Cortex of Rats Involves Serotonergic and Opioid Mechanisms in the Anterior Pretectal Nucleus

The electrical stimulation of the occipital (OC) or retrosplenial (RSC) cortex produces antinociception in the rat tail-flick test. These cortices send inputs to the anterior pretectal nucleus (APtN) which is implicated in antinociception and nociception. At least muscarinic cholinergic, opioid, and serotonergic mechanisms in the APtN are involved in stimulation-produced antinociception (SPA) from the nucleus. In this study, the injection of 2% lidocaine (.25 μL) or methysergide (40 and 80 ng/.25 μL) into the APtN reduced the duration but did not change the intensity of SPA from the OC, whereas both duration and intensity of SPA from the RSC were significantly reduced in rats treated with lidocaine or naloxone (10 and 50 ng/.25 μL), injected into the APtN. Naloxone or methysegide injected into the APtN was ineffective against SPA from the OC or RSC, respectively. Atropine (100 ng/.25 μL) injected into the APtN was ineffective against SPA from either the OC or RSC. We conclude that the APtN acts as an intermediary for separate descending pain inhibitory pathways activated from the OC and RSC, utilizing at least serotonin and endogenous opioid as mediators in the nucleus. PerspectiveStimulation-induced antinociception from the retrosplenial or occipital cortex in the rat tail-flick test depends on the activation of separate descending pain inhibitory pathways that utilize the APtN as a relay station.

Endogenous Opioids Inhibit Early-Stage Pancreatic Pain in a Mouse Model of Pancreatic Cancer

The endogenous opioid system is involved in modulating the experience of pain, the response to stress, and the action of analgesic therapies. Recent human imaging studies have shown a significant tonic modulation of visceral pain, raising the question of whether endogenous opioids tonically modulate the pain of visceral cancer. Transgenic mice expressing the first 127 amino acids of simian virus 40 large T antigen, under the control of the rat elastase-1 promoter, that spontaneously develop pancreatic cancer were used to investigate the role of endogenous opioids in the modulation of pancreatic cancer pain. Visceral pain behaviors were assessed as degree of hunching and vocalization. Although mice with late-stage pancreatic cancer displayed spontaneous, morphine-reversible, visceral pain-related behaviors such as hunching and vocalization, these behaviors were absent in mice with early-stage pancreatic cancer. After systemic administration of the central nervous system (CNS)-penetrant opioid receptor antagonists naloxone or naltrexone, mice with early-stage pancreatic cancer displayed significant visceral pain-related behaviors, whereas systemic administration of the CNS-nonpenetrant opioid antagonist naloxone-methiodide did not induce an increase in visceral pain behaviors. Our findings suggest that a CNS opioid-dependent mechanism tonically modulates early and late-stage pancreatic cancer pain. Understanding the mechanisms that mask this pain in early stage disease and drive this pain in late-stage disease may allow improved diagnosis, treatment, and care of patients with pancreatic cancer.

Update on cluster headache.

Although cluster headache has traditionally been thought of as a vascular headache disorder, its periodicity suggests an involvement of central areas such as the hypothalamus. This review covers the past 3 years, which have seen remarkable progress in understanding the pathophysiology of circadian headache syndromes and have brought exciting news. As more cluster headache patients are seen by headache specialists, new forms of this well-defined primary headache syndrome are being identified. In addition, we discuss recent findings with regard to abnormalities in the secretion of hormones, genetic influences, neuroimaging of cluster headache attacks, and the use of newer substances as preventive therapy in cluster headache. We have entered a new diagnostic and therapeutic era in primary headache disorders. In recent reports, the use of deep brain stimulation of the hypothalamus has enabled intractable chronic cluster headache patients to be successfully operated upon. Further research in this field is urgently needed and the recent possibility of combining deep brain stimulation with positron emission tomography will certainly help to unravel the brain circuitry implicated in stimulation-produced analgesia. The time has come to use the evidence for a disorder of circadian rhythm in cluster headache to further the development of chronobiotics in the treatment of this disorder.

Unchanged c-Fos expression after extracorporeal shock wave therapy: an experimental investigation in rats.

Despite the extensive use of extracorporeal shock wave therapy (ESWT) in the therapy of chronic tendopathies, the biological mechanisms of its antinociceptive effects are still unclear. In this study we addressed the question of whether the clinically described, long-lasting effect of ESWT is mediated by changes in the activity of spinal cord neurones. As a marker for neuronal activity which is also able to interfere with the molecular expression pattern of neurones, the expression of the inducible transcription factor c-Fos was analysed in the animal model of the rat. Despite application of different energy levels, the analysis of c-Fos protein expression at an early (4 h) and late (72 h) time point after ESWT revealed no visible changes in immunoreactivity in the dorsal horn of the spinal cord. Additionally, there was no change in c-Fos protein and its gene expression c-Fos mRNA in the treatment area of the paw. We conclude that ESWT with an energy flux dose up to 0.33 mJ/mm(2)does not modify neuronal activity. Since the application of ESWT showed no significant changes in the immunoreactivity of c-Fos, it is therefore unlikely that ESWT triggers stimulation-produced analgesia via activation of peripheral nerves.

Effects of a kappa agonist, spiradoline mesylate (U62,066E), on activation and vaginocervical-stimulation produced analgesia in rats

Previous research has demonstrated increased pain threshold during copulation, gestation, and parturition in animals. In the laboratory, mechanostimulation of the vaginocervical region in many animals, as well as humans, can increase responsiveness to noxious but not to innocuous stimuli. This increased pain inhibition to vaginocervical stimulation, which mimics natural parturition, is mediated by spinal and supraspinal neuropeptides, including the opiates. The present research was designed to ascertain the possible effects of a kappa opioid agonist on vaginocervical-stimulated analgesia in rats. Initially, the novel kappa-selective agonist, spiradoline mesylate (U62,066E; 0, 0.1, 1.0, 10.0 mg/kg, i.p.), was injected intraperitoneally and general behavioral arousal in an open field apparatus was recorded. Results from this experiment indicate that stimulation with the kappa-selective drug caused significant decreases in behavioral activity at the high dose as compared to saline and the medium and low doses. Next, the effects of U62,066E (0, 0.1, 1.0, 10.0 mg/kg, i.p.) on the analgesia associated with vaginocervical stimulation were determined in a tail flick apparatus. The kappa drug significantly increased antinociceptive thresholds prior to and during vaginocervical stimulation at the 0.1 and 1.0 mg/kg doses. By contrast, the high dose (10.0 mg/kg) of U62,066E decreased vaginocervical stimulation-produced analgesia. Results are discussed in terms of the potential of nonaddictive kappa-selective opioid compounds being utilized in reproductive pain.

Stimulation of human thalamus for pain relief: possible modulatory circuits revealed by positron emission tomography.

Stimulation of human thalamus for pain relief: possible modulatory circuits revealed by positron emission tomography. J. Neurophysiol. 80: 3326-3330, 1998. Stimulation of the somatosensory thalamus was used for more than 2 decades to treat chronic pain in the human. However, despite clinical reports of successful results, little is known about the actual mechanisms mediating this form of stimulation-produced analgesia. To reveal possible neuronal pathways evoked by thalamic stimulation, we measured regional changes in cerebral blood flow (rCBF) in five patients who received successful long-term relief of chronic pain with somatosensory thalamic stimulation. Positron emission tomography during thalamic stimulation revealed significant activation of the thalamus in the region of the stimulating electrodes as well as activation of the insular cortex ipsilateral to the thalamic electrodes (contralateral to the patients' clinical pain). For these patients, thalamic stimulation also evoked paresthesiae that included thermal sensations in addition to tingling sensations. Results of this study indicate that in some cases somatosensory thalamic stimulation may activate a thalamocortical pain modulation circuit that involves thermal pathways. These results are consistent with other recent reports suggesting that activation of thermal pathways may contribute to modulation of nociceptive information.

Self-injurious behaviour and body site preference.

Self-injury by people with intellectual disabilities is a highly problematic and damaging behaviour with profound implications for quality of life. To date, very little detailed descriptive information has been available on the distribution and location of body sites that are injured. This study presents preliminary information on the locations of the self-injury body sites of 29 school-age individuals with developmental and intellectual disabilities who self-injured daily. Teaching staff in school-based special education programmes independently recorded the body locations of where their student's self-injured. Approximately 80% of the reported self-injury was directed disproportionately toward the head and hands. Three-quarters of head-directed self-injury was located on the front of the head, and 83% of hand-directed self-injury was located on the back of the hands. Furthermore, 32% of the body sites toward which self-injury was directed were located on stimulation-produced analgesia body sites. The implications of these findings are discussed in relation to the opioid hypothesis of self-injurious behaviour, and with regard to future research investigating functional diagnostic strategies considering both social and biological variables.

Stimulation of the central and peripheral nervous system for the control of pain.

After suffering some setbacks since its introduction in 1967, stimulation of the spinal and peripheral nervous systems has undergone rapid development in the last ten years. Based on principles enunciated in the Gate Control Hypothesis that was published in 1968, stimulation-produced analgesia [SPA] has been subjected to intensive laboratory and clinical investigation. Historically, most new clinical ideas in medicine have tended to follow a three-tiered course. Initial enthusiasm gives way to a reappraisal of the treatment or modality as side-effects or unanticipated problems arise. The last and third phase proceeds at a more measured pace as the treatment is refined by experience. This review is divided into three parts as it traces the progress of spinal cord stimulation [SCS] and peripheral nerve stimulation [PNS]. The review commences with a discussion of the theory of SCS and PNS, and is followed by early reports during which it became apparent that the modality is essentially only effective in the treatment of neuropathic pain. The last section describes the modern experience including efficacy in specific types of pain and concludes with recent accomplishments that dramatize the relief of pain which can be achieved in nonoperable peripheral vascular disease or myocardial ischemia. Over the years, a search for those transmitters that might be influenced by spinal cord stimulation focused on somatostatin, cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP), neurotensin and other amines, although only substance "P" was implicated. More recently, in animal studies, evidence that GABA-ergic systems are affected may explain the frequent successful suppression of allodynia that follows spinal cord stimulation. During the past eight years, much attention has been directed to studies that use a chronic neuropathic pain model. While PNS held significant promise as a pain relieving modality, early electrode systems and their surgical implantation yielded variable results due to evolving technical and surgical skills. These results dramatically reduced the continued development of PNS, which then gave way to a preoccupation with SCS. Modern development of SCS with outcome studies, particularly in relation to failed back surgery syndrome [FBSS] and the outcome of peripheral nerve surgery for chronic regional pain syndromes, has earned both modalities a place in the ongoing management of patients with intractable neuropathic pain. The last section, dealing with pain of peripheral vascular and myocardial ischemia, is perhaps one of the more exciting developments in stimulation produced analgesia and as the papers discussed demonstrate, can provide a level of analgesia and efficacy that is unattainable by other treatment modalities. SCS and PNS has an important role to play in the management of conditions that are otherwise refractory to conservative or other conventional management.

Rats with decreased brain cholecystokinin levels show increased responsiveness to peripheral electrical stimulation-induced analgesia

Using the P77PMC strain of rat, which is genetically prone to audiogenic seizures, and also has decreased levels of cholecystokinin (CCK), we examined the analgesic response to peripheral electrical stimulation, which is, in part, opiate-mediated. A number of studies have suggested that CCK may function as an antagonist to endogenous opiate effects. Therefore, we hypothesized that the P77PMC animals would show an enhanced analgesic response based on their decreased CCK levels producing a diminished endogenous opiate antagonism. We found that the analgesic effect on tail flick latency produced by 100 Hz peripheral electrical stimulation was more potent and longer lasting in P77PMC rats than in control rats. Moreover, the potency of the stimulation-produced analgesia correlated with the vulnerability to audiogenic seizures in these rats. We were able to block the peripheral electrical stimulation-induced analgesia (PSIA) using a cholecystokinin octapeptide (CCK-8) administered parenterally. Radioimmunoassay showed that the content of CCK-8 in cerebral cortex, hippocampus and periaqueductal gray was much lower in P77PMC rat than in controls. These results suggest that low CCK-8 content in the central nervous system of the P77PMC rats may be related to the high analgesic response to peripheral electrical stimulation, and further support the notion that CCK may be an endogenous opiate antagonist.

Mechanism of transmission and modulation of renal pain in cats; effect of nucleus raphe magnus stimulation on renal pain.

Initially, when periaqueductal gray (PAG) is electrically stimulated, analgesia is induced, and this phenomenon is called stimulation-produced analgesia. Nucleus raphe magnus (NRM) as well as PAG are known to be the potent analgesic centers. NRM could modulate the nociceptive response of spinal cord neurons through spinally projecting fibers. However, as well as the above analgesic effects have been confined to the somatic pain, it was variable according to species, and the analgesic effect by NRM stimulation on the visceral pain was not yet clarified. In this study the analgesic effect by NRM stimulation on the visceral pain was examined through recording the activities of the dorsal horn neurons with renal input and renal pain, as a type of visceral pain. The renal pain was induced by ureteral occlusion or renal arterial occlusion, which in turn activated the renal mechanoreceptor or chemoreceptor. These cells had concomitant somatic input. In order to compare the effects of NRM stimulation on the renal pain with somatic pain, the somatic stimulation such as squeezing was conducted on the peripheral receptive field. The main results are summarized as follows: 1) After an electrical stimulation of NRM, spontaneous activities of dorsal horn neurons with renal input were reduced to 73.3 +/- 9.7% of the control value. 2) After an electrical stimulation of NRM, activities of dorsal horn neurons with renal input evoked by a brush, a type of non-noxious stimuli, did not change significantly. But the activities by a squeeze, a type of noxious stimuli, the activities were reduced to 63.2 +/- 7.2% of the control value. 3) After an electrical stimulation of NRM, activities of dorsal horn neurons with renal input evoked by occlusion of ureter or renal artery were reduced to 46.7 +/- 8.8% and 49.0 +/- 8.0% of the control value respectively. 4) The inhibitory effect of NRM on the dorsal horn neurons with renal input did not show any difference between renal A delta fiber and C fiber group. 5) By the electrical stimulation of NRM, the activities evoked by ureteral occlusion showed more reduction in the high threshold cell group than in the wide dynamic range cell group. These results suggest that activation of NRM can alleviate the renal pain as well as the somatic pain by modulating the dorsal horn neurons activities.

Role of norepinephrine in the interaction between the lateral reticular nucleus and the nucleus raphe magnus: an electrophysiological and behavioral study

We have previously demonstrated that the nucleus raphe magnus (NRM) sends a predominantly inhibitory projection to the lateral reticular nucleus (LRN); however, the pharmacology of this pathway is not known. The purpose of this study was to examine the role of norepinephrine in the NRM-LRN system using both electrophysiological and behavioral techniques. Sixty-nine LRN cells were recorded extracellularly. Cells were tested for their response to noxious and innocuous peripheral stimulation applied to the dorsal body surface. The majority of cells were classified as wide dynamic range, with inhibition being the predominant response; receptive fields were located primarily on the tail and hind limbs. The effect of excitatory amino acid glutamate (GLU) administration into NRM (GLU-NRM) was tested on all 69 cells. GLU-NRM inhibited 55 of 69 LRN cells tested; 7 cells were excited and 7 cells did not respond. Thirty-nine LRN cells were tested for their response to norepinephrine (NE) iontophoretically applied in LRN (NE-LRN). Two distinct types of effects were noted. In 9 cells, both NE-LRN and GLU-NRM produced a strong inhibition, with the magnitude of effect between the 2 drugs significantly correlated. In a second group of cells (n = 12), GLU-NRM produced an inhibitory effect while NE-LRN had no effect on the cells' baseline firing rate. However, when the 2 drugs were applied simultaneously, NE-LRN blocked the inhibitory effects of NRM stimulation. The effect of the α 2-receptor antagonist yohimbine (YOH) on NRM-evoked responses was tested in 30 LRN cells. The majority of these cells were inhibited by GLU-NRM. Similar to the dichotomous effect noted by NE-LRN, YOH applied iontophoretically in LRN (YOH-LRN) had two predominant effects on NRM-produced inhibition. In 14 of 27 cells, YOH-LRN significantly potentiated the inhibitory effects of NRM stimulation by increasing the duration of the inhibitory epoch an average of 100 sec. In 7 of 27 cells, YOH directly applied in LRN partially antagonized NRM-evoked inhibition. In a second series of experiments, microinjection cannulas were placed within NRM and LRN in order to determine the effect of blocking α 2-receptor activity within LRN on NRM stimulation-produced analgesia in an intact animal. Administration of d,l-homocysteic acid in NRM resulted in a significant increase in baseline tail-flick latency of approximately 140%. Pretreatment with YOH (3 μg in 0.5 μl) in LRN resulted in a significant potentiation of this analgesic effect. These results indicate that NRM sends a predominantly inhibitory projection to the LRN that involves noradrenaline and that this pathway is functionally active in an awake, behaving animal.

Direct projections from the midbrain periaqueductal gray and the dorsal raphe nucleus to the trigeminal sensory complex in the rat

It is well known that analgesia can be produced by stimulation of the midbrain periaqueductal gray and dorsal raphe nucleus. This stimulation-produced analgesia may operate, at least partly, through direct projections to nociceptors in the primary sensory nuclei. In the present study, direct projections from the midbrain periaqueductal gray and dorsal raphe nucleus to the trigeminal sensory complex were studied in the rat. After injection of Phaseolus vulgaris leucoagglutinin into the periaqueductal gray or dorsal raphe nucleus, terminal labeling was found in the principal sensory trigeminal nucleus and the oral, interpolar and caudal subnuclei of the spinal trigeminal nucleus, bilaterally with an ipsilateral predominance. The terminal labeling was prominent in the ventrolateral parts of the trigeminal sensory complex; it was particularly marked in the principal sensory trigeminal nucleus and laminae I and III of the caudal subnucleus of the spinal trigeminal nucleus. After injection of cholera toxin B subunit into the principal sensory trigeminal nucleus or one of the subnuclei of the spinal trigeminal nucleus, retrogradely labeled cells were seen in the periaqueductal gray and dorsal raphe nucleus, bilaterally with an ipsilateral dominance. In the periaqueductal gray they were most often seen in the ventrolateral and dorsolateral subdivisions, but no particular topographic organization was detected in the distribution of retrogradely labeled neurons in the periaqueductal gray and dorsal raphe nucleus after tracer injection into each subdivision of the trigeminal sensory complex. After injections of Fast Blue and Diamidino Yellow, respectively, into the principal sensory trigeminal nucleus and the caudal subnucleus of the spinal trigeminal nucleus on one side of the brain, a number of doubly labeled neurons were found in the periaqueductal gray and dorsal raphe nucleus, bilaterally with an ipsilateral dominance. The results indicate that a considerable number of neurons in the periaqueductal gray and dorsal raphe nucleus send projection fibers to the trigeminal sensory complex, and that some of them send their axons to both the principal sensory trigeminal nucleus and the caudal subdivision of the spinal trigeminal nucleus by way of axon collaterals. These projections may subserve suppression of the activity of nociceptive neurons in the trigeminal system.

Periaqueductal gray matter stimulation-produced analgesia in diabetic rats

The effect of diabetes on periaqueductal gray matter (PAG) stimulation-produced analgesia (SPA) was examined in rats. PAG SPA was assessed using the tail-pinch test. PAG stimulation produced marked analgesia in both naive and diabetic rats. Furthermore, the degree of PAG SPA did not differ between naive and diabetic rats. PAG SPA was significantly attenuated by a low dose (0.5 mg/kg, s.c.) of naloxone in naive rats, but not in diabetic rats. However, a high dose (5 mg/kg, s.c.) of naloxone significantly and equally attenuated PAG SPA in both naive and diabetic rats. On the other hand, the analgesic potency of morphine (3 mg/kg, s.c.) was significantly reduced in diabetic rats as compared with naive rats. These results suggest that PAG SPA in diabetic rats may be mediated by different opioid receptor interactions as compared with naive rats.

Positive feedback action of pituitary β-Endorphin on acupuncture analgesia afferent pathway

Potentials in the final sector of the afferent pathway from the acupuncture point (AP) were enhanced by intraperitoneal 0.5 mg/kg morphine without changing the threshold of AP stimulation and greatly decreased by hypophysectomy. The decreased potentials were restored to the control level by morphine (0.5 mg/kg, IP). Potentials evoked in the final sector of the afferent pathway from the nonacupuncture point (NAP) by NAP stimulation after lesion of the analgesia inhibitory system were greatly enhanced by corticotropin (ACTH) (0.25 mg/kg, IP) and greatly decreased by hypophysectomy. Diminished potentials were restored to the control level by ACTH (0.25 mg/kg, IP). Both morphine (0.5 mg/kg, IP) and ACTH (0.25 mg/kg, IP) produced analgesia, but morphine did not affect acupuncture analgesia (AA) and ACTH did not affect nonacupuncture point stimulation-produced analgesia (NAA). All analgesia, that due to 0.5 mg/kg morphine or 0.25 mg/kg ACTH, AA, and NAA were abolished by hypophysectomy. The abolished AA and NAA were restored by 0.5 mg/kg morphine and 0.25 mg/kg ACTH, respectively. Hence, β-E and ACTH liberated from the pituitary gland by stimulation of an AP and NAP may act as positive feedback on the AA and NAA afferent pathways, respectively.

Treatment of Chronic Pain by Epidural Spinal Cord Stimulation

Epidural spinal cord stimulation by means of chronically implanted electrodes was carried out on 121 patients with pain of varied benign organic etiology. In 116 patients, the pain was confined to the back and lower extremities and, of these, 56 exhibited the failed-back syndrome. Most patients were referred by a pain management service because of failure of conventional pain treatment modalities. Electrodes were implanted at varying sites, dictated by the location of pain. A total of 140 epidural implants were used: 76 unipolar, 46 Resume electrodes, 12 bipolar, and six quadripolar. Patients were followed for periods ranging from 6 months to 10 years, with a mean follow-up period of 40 months. Forty-eight patients (40%) were able to control their pain by neurostimulation alone. A further 14 patients (12%), in addition to following a regular stimulation program, needed occasional analgesic supplements to achieve 50% or more relief of the prestimulation pain. Pain secondary to arachnoiditis or perineural fibrosis following multiple intervertebral disc operations, when predominantly confined to one lower extremity, seemed to respond favorably to this treatment. Uniformly good results were also obtained in lower-extremity pain secondary to multiple sclerosis. Pain due to advanced peripheral vascular disease of the lower limbs was well controlled, and amputation below the knee was delayed for up to 2 years in some patients. Pain due to cauda equina injury, paraplegic pain, phantom-limb pain, pure midline back pain without radiculopathy, or pain due to primary bone or joint disease seemed to respond less well. Patients who responded to preliminary transcutaneous electrical nerve stimulation generally did well with electrode implants. Notable complications included wound infection, electrode displacement or fracturing, and fibrosis at the stimulating tip of the electrode. Three patients in this series died due to unrelated causes. Epidural spinal cord stimulation has proven to be an effective and safe means of controlling pain on a long-term basis in selected groups of patients. The mechanism of action of stimulation-produced analgesia remains unclear; further studies to elucidate it might allow spinal cord stimulation to be exploited more effectively in disorders that are currently refractory to this treatment modality.

The development of stimulation-produced analgesia (SPA) in the rat

The present study studied the development of stimulation produced analgesia (SPA) from the periaqueductal gray (PAG) in rats. A monopolar stimulating electrode was lowered into the dorsal or ventral PAG of animals aged 7, 14, 21, or 90–120 days. Constant current cathodal pulses (100 Hz, 100 μs) were delivered, starting 10 s before analgesia was tested by the tail-flick (TF) test and continuing throughout each TF trial or until cut-off (7 s). Current intensity was increased stepwise (3–200 μA). It was found that SPA can be elicited starting at 21 days, but not earlier. However, supraspinal modulation of nociception is still immature at 3 weeks after birth. First, stimulation intensities needed to produce SPA are higher in 21-day-old pups than in adult animals. Second, in 21-day-old pups, but not in adults effective current intensities in the dorsal PAG are higher than in the ventral PAG. Third, naltrexone decreases SPA from the ventral PAG in 21-day-old pups, but not in adult animals. These findings indicate that supraspinal modulation of nociception develops only 3 weeks after birth, with the ventral PAG maturing prior to the dorsal PAG, and that the contribution of endogenous opioids to SPA does not remain constant throughout the ontogeny of rats.

Treatment of chronic pain by epidural spinal cord stimulation: a 10-year experience

Epidural spinal cord stimulation by means of chronically implanted electrodes was carried out on 121 patients with pain of varied benign organic etiology. In 116 patients, the pain was confined to the back and lower extremities and, of these, 56 exhibited the failed-back syndrome. Most patients were referred by a pain management service because of failure of conventional pain treatment modalities. Electrodes were implanted at varying sites, dictated by the location of pain. A total of 140 epidural implants were used: 76 unipolar, 46 Resume electrodes, 12 bipolar, and six quadripolar. Patients were followed for periods ranging from 6 months to 10 years, with a mean follow-up period of 40 months. Forty-eight patients (40%) were able to control their pain by neurostimulation alone. A further 14 patients (12%), in addition to following a regular stimulation program, needed occasional analgesic supplements to achieve 50% or more relief of the prestimulation pain. Pain secondary to arachnoiditis or perineural fibrosis following multiple intervertebral disc operations, when predominantly confined to one lower extremity, seemed to respond favorably to this treatment. Uniformly good results were also obtained in lower-extremity pain secondary to multiple sclerosis. Pain due to advanced peripheral vascular disease of the lower limbs was well controlled, and amputation below the knee was delayed for up to 2 years in some patients. Pain due to cauda equina injury, paraplegic pain, phantom-limb pain, pure midline back pain without radiculopathy, or pain due to primary bone or joint disease seemed to respond less well. Patients who responded to preliminary transcutaneous electrical nerve stimulation generally did well with electrode implants. Notable complications included wound infection, electrode displacement or fracturing, and fibrosis at the stimulating tip of the electrode. Three patients in this series died due to unrelated causes. Epidural spinal cord stimulation has proven to be an effective and safe means of controlling pain on a long-term basis in selected groups of patients. The mechanism of action of stimulation-produced analgesia remains unclear; further studies to elucidate it might allow spinal cord stimulation to be exploited more effectively in disorders that are currently refractory to this treatment modality.

Management of sympathetic pain

Successful treatment of sympathetic pain is directed at the restoration of normal function. This can be achieved in the majority of cases with a combination of appropriate sympathetic or somatic nerve block, usually coupled with aggressive physiotherapy. It is a matter of regret that there are few controlled trials to demonstrate the efficacy of any of these forms of management. Other non-invasive techniques such as stimulation-produced analgesia and pharmacology, particularly the use of adrenergic blocking agents, hold some promise of future benefit. Here too, more effort should be made to carry out properly designed studies, as there is scepticism about the place of permanent or potentially destructive therapy in any painful condition.