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Damage to nociceptor nerve fibres may give rise to peripheral neuropathies, some of which are pain free and some are painful. A hallmark of many peripheral neuropathies is the loss of small nerve fibres in the epidermis, a condition called small-fibre neuropathy (SFN) when it is predominantly the small nerve fibres that are damaged. Historically, SFN has been very difficult to diagnose as clinical examination and nerve conduction studies mainly detect large nerve fibres, and quantitative sensory testing is not sensitive enough to detect small changes in small nerve fibres. However, taking a 3-mm punch skin biopsy from the distal leg and quantification of the nerve fibre density has proven to be a useful method to diagnose SFN. However, the correlation between the nerve fibre loss and other test results varies greatly. Recent studies have shown that it is possible not only to extract information about the nerve fibre density from the biopsies but also to get an estimation of the nerve fibre length density using stereology, quantify sweat gland innervation and detect morphological changes such as axonal swelling, all of which may be additional parameters indicating diseased small fibres relating to symptoms reported by the patients. In this review, we focus on available tests to assess structure and function of the small nerve fibres, and summarize recent advances that have provided new possibilities to more specifically relate structural findings with symptoms and function in patients with SFN., (© 2014 European Pain Federation - EFIC®)

Background: Nerve injury is a main cause of long-term morbidity following blood donation, but little is known about symptoms, impact, prognosis and underlying cause., Materials and Methods: A questionnaire, designed to characterize pain and estimate the prevalence of neuropathic pain, was sent to all blood donors registered with a complication related to 3 297 674 blood donations in Denmark from 2000-2009, with a local complication mainly characterized by pain, with severity grade 'long-term morbidity' and imputability grade 'definite' or 'probably'., Results: The questionnaire was sent to 152 donors (4·6 per 100 000 donations). Response rate was 88/152 (57·9%). At the time of the questionnaire, which was between 12 months and 10 years after the blood donation, 69/88, who responded (78·4%) still experienced symptoms. Of the 69 donors with persistent symptom, pain occurred in 51 donors (74%) was moderate to severe in 24/69 donors (35%) and had an impact on daily activity in 17/69 (25%). Neuropathic pain was estimated to be the underlying cause of symptom in 30-52% of the 69 donors with persistent symptoms, using three different systems for estimation, corresponding to 0·6-1·1/100 000 donations., Discussion: Although a rare complication, nerve injury after blood donation may lead to long-term morbidity and may become chronic in a small proportion of donors. The most common symptoms are pain, and we estimate that neuropathic pain can be the underlying cause., (© 2015 International Society of Blood Transfusion.)

Background: Corticomotor excitability has been shown to correlate with motor learning and functional recovery. The aim of the present study was to monitor changes in excitability of the corticomotor pathways induced by neck training and to compare the effects in patients with neck or knee pain and pain-free participants., Methods: Corticomotor excitability was assessed using transcranial magnetic stimulation and electromyography at baseline, after 30 min and 1 h, and at a 1-week follow-up visit. The primary outcome measures were changes in amplitudes and latencies of motor evoked potentials (MEPs) at 1-week follow-up., Results: MEP responses induced by neck training yielded significantly different outcomes in the three groups. In the group with neck pain and training, MEP amplitudes were significantly reduced between baseline and 30 min (p ≤ 0.05), but with no significant difference between baseline, 1 h (p = 0.178) and 1 week (p = 0.067). In the group with knee pain and training, MEP amplitudes significantly increased between baseline and 30 min (p ≤ 0.01) and 1 h (p < 0.001), but not after 1 week (p = 0.524) compared with baseline. In the pain-free group, there were no changes over time., Conclusion: Neck training reduced neuroplastic responsiveness of corticomotor pathways in neck pain patients in contrast to knee pain patients and pain-free participants. Increased attention to adaptive and maladaptive neuroplastic responses induced by training may prove valuable in the process of optimizing clinical outcomes., (© 2014 European Pain Federation - EFIC®)

Background: Post-stroke pain is common and affects the quality of life of stroke survivors, but the incidence and severity of headache, shoulder pain, other joint pain and central post-stroke pain following stroke still remain unclear. The aim of this prospective study was to determine the incidence and intensity of these different types of post-stroke pain., Methods: A total of 299 consecutive stroke patients, admitted to the Department of Neurology at Aarhus University Hospital, underwent a structured interview and a short sensory examination within 4 days of admission. Follow-up was conducted by phone 3 and 6 months after stroke onset, with 275 patients completing the whole study. Pain with onset in relation to stroke onset or following stroke was defined as 'newly developed pain'., Results: At the 6-month follow-up, newly developed pain was reported by 45.8% of the patients; headache by 13.1%, shoulder pain by 16.4%, other joint pain by 11.7%, other pain by 20.0% and evoked pain by light touch or thermal stimuli by 8.0%. More than one pain type was reported by 36.5% of the patients with newly developed pain. According to pre-defined criteria, 10.5% of the patients were classified as having possible central post-stroke pain. There was a moderate to severe impact on daily life in 33.6% of the patients with newly developed pain., Conclusions: Pain following stroke is common, with almost half of the patients reporting newly developed pain 6 months after stroke., (© 2012 European Federation of International Association for the Study of Pain Chapters.)

Treatment outcome in patients with neuropathic pain (NP) is often variable and disappointing. We tested the hypothesis that patients with clear evidence of nervous system lesion respond better to pharmacological treatment with documented effect on NP than patients with poor or no evidence of nervous system lesion. Furthermore, we examined whether specific symptoms or signs were associated with treatment outcome. A total of 214 patients with suspected non-cancer NP were divided into four groups with graded evidence of nervous system lesion based on medical history, bedside sensory examination, quantitative sensory tests, electrophysiology, and neuroimaging. Patients were treated with imipramine guided by plasma-drug concentrations. Gabapentin 2400 mg/day was given in case of treatment failure or if imipramine treatment was not possible. Two hundred patients completed the study. Global pain relief was similar in the four groups. There was no association between evidence of nervous system lesion and treatment outcome. Classical NP signs: abnormal temporal summation, cold and brush allodynia, and abnormal sensibility to temperature were also unrelated to outcome. Treatment outcome was similar in peripheral and central definite NP. Neither definite evidence of nervous system lesion nor abnormal sensory phenomena seems to predict for good outcome of therapy with imipramine or gabapentin in patients with suspected neuropathic pain.

Itch sensation can be inhibited by simultaneously applied cutaneous pain at the same skin site via a central mechanism. Deep muscle pain is often associated with sensory changes in the corresponding dermatome. We investigated whether experimentally induced muscle pain has any influence on histamine-induced itch and vice versa in a double blind placebo-controlled study. Experiments were performed in 18 healthy subjects. In nine individuals control iontophoresis of histamine into the forearm produced a distinct itch sensation. Another nine individuals participated in an additional experiment in which histamine and saline were iontophoresed on the forearm in a randomized double-blinded two-way crossover design after intramuscular injection of capsaicin into the ipsilateral brachioradial muscle. Capsaicin-induced muscle pain reduced itch sensation significantly. In contrast, capsaicin-induced muscle pain increased significantly after cutaneous histamine application compared to muscle pain after iontophoresis of saline (placebo). These novel data indicate that muscle pain inhibits itch and histamine increases muscle pain. A bi-directional interaction between cutaneous histamine-sensitive afferents and nociceptive muscle afferents via central mechanisms is suggested.

Aim: Do distraction from- or attention to sural nerve stimulation affect pain, heart rate variability, and a spinal withdrawal reflex?, Material and Methods: In 26 male volunteers, electrical stimulation at the distal cutaneous receptive field of the sural nerve elicited pain and a nociceptive withdrawal reflex. Intensity of pain was rated on a numeric rating scale. Electromyographic reflex responses were measured from biceps femoris muscle. Cardiac autonomic function was estimated by heart rate variability measures and was expressed in the time domain as mean of RR-intervals for normal heart beats (mean-RR) and standard deviation of all normal RR-intervals (SD-NN) and, in the frequency domain, where pure vagal activity was assessed by high frequency power (0.15-0.4 Hz). Low frequency power (0.04-0.15 Hz) reflects both parasympathetic and sympathetic control. Effect parameters were recorded before and during random distraction and attention. Distraction from sural nerve stimulation was induced by a mental arithmetic test, paced auditory serial addition task (PASAT), while attention was induced by concentrating on painful foot stimulation., Results: Paced auditory serial addition task decreased mean-RR and SD-NN, frequency domain parameters, as well as pain (P<0.001). In contrast, PASAT did not change the spinal withdrawal reflex. Attention did not affect any effect parameter., Conclusion: Distraction by PASAT altered autonomic activity and inhibited pain but failed to affect withdrawal reflex responses, while attention had no effect on either parameter. Psychological distraction and attention may have different effects on noxious evoked pain perception and autonomic activity. Pain relief during PASAT probably involves supraspinal mechanisms.

Background: A new pain questionnaire should be simple, be documented to have discriminative function, and be related to previously used questionnaires., Methods: Word meaning was validated by using bilingual Danish medical students and asking them to translate words taken from the Danish version of the McGill pain questionnaire into English. Evaluative word value was estimated using a visual analog scale (VAS). Discriminative function was assessed by having patients with one of six painful conditions (postherpetic neuralgia, phantom limb pain, rheumatoid arthritis, ankle fracture, appendicitis, or labor pain) complete the questionnaire., Results: We were not able to find Danish words that were reliably back-translated to the English words 'splitting' or 'gnawing'. A simple three-word set of evaluative terms had good separation when rated on a VAS scale ('let' 17.5+/-6.5 mm; 'moderat' 42.7+/-8.6 mm; and 'staerk' 74.9+/-9.7 mm). The questionnaire was able to discriminate among the six painful conditions with 77% accuracy by just using the descriptive words. The accuracy of the questionnaire increased to 96% with the addition of evaluative terms (for pain at rest and with activity), chronicity (acute vs. chronic), and location of the pain., Conclusions: A Danish pain questionnaire that subjects and patients can self-administer has been developed and validated relative to the words used in the English McGill Pain questionnaire. The discriminative ability of the questionnaire among some common painful conditions has been tested and documented. The questionnaire may be of use in patient care and research.

In September 2001, a Task Force was set up under the auspices of the European Federation of Neurological Societies with the aim of evaluating the existing evidence about the methods of assessing neuropathic pain and its treatments. This review led to the development of guidelines to be used in the management of patients with neuropathic pain. In the clinical setting a neurological examination that includes an accurate sensory examination is often sufficient to reach a diagnosis. Nerve conduction studies and somatosensory-evoked potentials, which do not assess small fibre function, may demonstrate and localize a peripheral or central nervous lesion. A quantitative assessment of the nociceptive pathways is provided by quantitative sensory testing and laser-evoked potentials. To evaluate treatment efficacy in a patient and in controlled trials, the simplest psychometric scales and quality of life measures are probably the best methods. A laboratory measure of pain that by-passes the subjective report, and thus cognitive influences, is a hopeful aim for the future.

In spinal cord injury (SCI), pain is a major cause of disability. A review of experimental and human studies, which provide insight into the mechanisms and treatment of SCI neuropathic pain are presented. Each of a series of pathophysiologic changes after SCI may be relevant for the development of SCI neuropathic pain. These changes are discussed in relation to neuropathic pain at and below the level of SCI. SCI neuropathic pain is difficult to treat. Experimental and human randomized, double-blind, placebo-controlled, clinical trials on pharmacologic treatment of SCI pain are summarized.

Patients with spinal cord injury (SCI) may or may not develop central neuropathic pain despite having cord lesions of apparently the same site, extension and nature. The consequences of the cord lesion in the central nervous system and the mechanisms underlying pain are unclear. In this study, we examined sensory detection and pain thresholds above injury level in 17 SCI patients with central neuropathic pain, in 18 SCI patients without neuropathic pain, and in 20 control subjects without injury and pain. The SCI pain group had significantly higher cold and warm detection thresholds compared with the SCI pain free group and controls and higher tactile detection thresholds compared with the SCI pain free group. No difference in pain or pain tolerance thresholds was seen among pain and pain free SCI patients. These data suggest changes in somatosensory function in dermatomes rostral to the segmental injury level linked to the presence of central neuropathic pain in SCI patients. The results are discussed in relation to current concepts of pain inhibitory and facilitating systems.

Spinal cord injury (SCI) frequently results in neuropathic pain. However, the pathophysiology underlying this pain is unclear. In this study, we compared clinical examination, quantitative sensory testing (QST) and somatosensory evoked potentials (SEPs) in SCI patients with and without pain below spinal lesion level, with a control group of 20 subjects without injury. All patients had a traumatic SCI with a lesion above T10; 20 patients presented with spontaneous central neuropathic pain below lesion level, and 20 patients had no neuropathic pain or dysaesthesia. Patients with and without pain had a similar reduction of mechanical and thermal detection and pain thresholds, and SEPs. SCI patients with central pain more frequently had sensory hypersensitivity (brush- or cold-evoked pain, dysaesthesia or pinprick hyperalgesia) in dermatomes corresponding to lesion level than SCI patients without pain. There was no difference in intensity of pain evoked by repetitive pinprick at lesion level between patient groups. There was a significant correlation between intensity of brush-evoked dysaesthesia at lesion level and spontaneous pain below lesion level of SCI. These data suggest that lesion of the spinothalamic pathway alone cannot account for central pain in SCI patients, and that neuronal hyperexcitability at injury or higher level may be an important mechanism for pain below injury level.

Objectives: The relationship between the masseter inhibitory reflex (MIR) and nociceptive processing in the trigeminal region was studied in 10 healthy subjects. Based on the known increase in perceived sensory intensity following repetitive stimulation of the nociceptive system, we examined the hypothesis that the MIR reflects noxious activity in the trigeminal system by determining the possible relation between changes in MIR and perceived sensory intensity., Methods: The MIR was quantitated and compared with psychophysical measures following repetitive peri-oral electrical stimulation (5 square wave pulses of 0.5ms repeated at 2Hz). In addition to the early (ES1) and late (ES2) periods of exteroceptive suppression, two periods with apparent excitation could be distinguished from the background electromyografical activity: (a) the inter-suppression period (ISP) between the ES1 and the ES2, and (b) the post-suppression period (PSP) after the ES2. A computer algorithm was used to detect and quantitate ES1, ES2, ISP, and PSP. The response variables were (a) onset latencies and (b) magnitudes of suppression (ES1 and ES2) and excitation (ISP and PSP)., Results: Consistent reduction of the magnitude of ES2 suppression in response to repetitive stimuli was observed below as well as above the pain detection threshold., Conclusions: The observed reduction of the magnitude of ES2 suppression is not specifically related to nociceptive processing. Habituation or net inhibitory effects on inhibitory pre-motor neurones (i.e. disinhibition) are possible mechanisms for the observed reduction of the magnitude of ES2 suppression after repetitive stimulation.

Neuropathic pains refer to a heterogeneous group of pain conditions characterised by lesion or dysfunction of the normal sensory pathways. Clinical characteristics include: delayed onset of pain after nervous system lesion, pain in area of sensory loss, spontaneous and different evoked types of pains. It has so far only been possible to classify these pains on basis of underlying cause or on anatomical location. The mechanisms underlying neuropathic pain are not yet clear, but neuronal hyperexcitability in those neurons that have lost their normal patterned input seems to be a common denominator for many, if not all types, of neuropathic pains. Along these lines, a mechanism-based classification has recently been proposed, which is an attractive approach because it provides a frame for a rationally based therapy of neuropathic pains. The clinical manifestations of neuronal hyperexcitability due to nervous system lesions is described.

Background: Painful trauma results in a disturbed metabolic state with impaired insulin sensitivity, which is related to the magnitude of the trauma. The authors explored whether pain per se influences hepatic and extrahepatic actions of insulin., Methods: Ten healthy male volunteers underwent two randomly sequenced hyperinsulinemic-euglycemic (insulin infusion rate, 0.6 mU x kg(-1) x min(-1) for 180 min) clamp studies 4 weeks apart. Self-controlled painful electrical stimulation was applied to the abdominal skin for 30 min, to a pain intensity of 8 on a visual analog scale of 0-10, just before the clamp procedure (study P). In the other study, no pain was inflicted (study C)., Results: Pain reduced whole-body insulin-stimulated glucose uptake from 6.37+/-1.87 mg x kg(-1) x min(-1) (mean +/- SD) in study C to 4.97+/-1.38 mg x kg(-1) x min(-1) in study P (P < 0.01) because of a decrease in nonoxidative glucose disposal, as determined by indirect calorimetry (2.47+/-0.88 mg x kg(-1) x min(-1) in study P vs. 3.41+/-1.03 mg x kg(-1) x min(-1) in study C; P < 0.05). Differences in glucose oxidation rates were not statistically significant. The suppression of isotopically determined endogenous glucose output during hyperinsulinemia tended to be decreased after pain (1.67+/-0.48 mg x kg(-1) x min(-1) in study P vs. 2.04+/-0.45 mg x kg(-1) x min(-1) in study C; P = 0.06). Pain elicited a twofold to threefold increase in serum cortisol (P < 0.01), plasma epinephrine (P < 0.05), and serum free fatty acids (P < 0.05). Similarly, circulating concentrations of glucagon and growth hormone tended to increase during pain., Conclusions: Acute severe pain decreases insulin sensitivity, primarily by affecting nonoxidative glucose metabolism. It is conceivable that the counterregulatory hormonal response plays an important role. This may indicate that pain relief in stress states is important for maintenance of normal glucose metabolism.

Within the last 2 decades there has been an explosion in new information on mechanisms underlying pain. Unfortunately this information has not resulted in a similar improvement of our handling of patients with chronic pain including chronic musculoskeletal pain. Neuronal hyperexcitability, which apparently is a key phenomenon in many (if not all) types of chronic pain results in changes in the nervous system from the level of the peripheral nociceptor to the highest cortical centers in the brain. The neuronal plastic changes in chronic pain conditions makes the nociceptive system amenable for treatment with several traditional as well as nontraditional types of interventions. Two treatment areas that seem worth exploring within chronic pain including headache concerns preventive measures and endogenous pain modulation.

A nociceptive withdrawal reflex in 12 human volunteers was elicited by painful electrical stimulation applied to the cutaneous innervation area of the sural nerve. The evoked electromyographic reflex activities were recorded with surface electrodes placed on the short head of the biceps femoris muscle ipsi-lateral to sural nerve stimulation, before, during and after conditioning stimuli. The nociceptive withdrawal reflex was conditioned by nociceptive and non-nociceptive, heterotopic and segmental counter-stimulation. Heterotopic nociceptive counter-stimulation and segmental nociceptive counter-stimulation were induced by ice water applied to the contra-lateral hand and foot, respectively. Heterotopic nociceptive counter-stimulation produced a significant inhibition of the nociceptive withdrawal reflex and the associated pains rating to sural nerve stimulation. Segmental nociceptive counter-stimulation inhibited the pain rating and tended to inhibit the nociceptive withdrawal reflex. There was no obvious correlation between visual analogue scale (VAS) and the nociceptive withdrawal reflex elicited by sural nerve stimulation neither in the group nor in the individual subject. This suggests that the nociceptive withdrawal reflex cannot always be used as a quantitative measure of pain.

Study Design: A postal survey., Objectives: To assess the prevalence and characteristics of pain and dysesthesia in a community based sample of patients with spinal cord injury (SCI) with special focus on neuropathic pain., Setting: Community. Western half of Denmark., Methods: We mailed a questionnaire to all outpatients (n = 436) of the Viborg rehabilitation centre for spinal cord injury. The questionnaire contained questions regarding cause and level of spinal injury and amount of sensory and motor function below this level. The words pain and unpleasant sensations were used to describe pain (P) and dysesthesia (D) respectively. Questions included location and intensity of chronic pain or dysesthesia, degree of interference with daily activity and sleep, presence of paroxysms and evoked pain or dysesthesia, temporal aspects, alleviating and aggravating factors, McGill Pain Questionnaire (MPQ) and treatment., Results: Seventy-six per cent of the patients returned the questionnaire, (230 males and 100 females). The ages ranged from 19 to 80 years (median 42.6 years) and time since spinal injury ranged from 0.5 to 39 years (median 9.3 years). The majority (> 75%) of patients had traumatic spinal cord injury. Of the respondents, 77% reported having pain or unpleasant sensations, and 67% had chronic pain or unpleasant sensations at or below lesion. Forty-eight per cent reported that P/D could be evoked by non-noxious stimulation of the skin indicating that allodynia is present in almost half of the patients. Forty-three per cent of respondents took analgesics, 7% received antidepressants or anticonvulsants., Conclusion: This survey suggests that pain and dysesthesia are common and serious complaints in SCI patients. Unexpectedly, only 7% of the patients were treated with drugs considered to be most effective in neuropathic pain. This emphasizes the need for a continued research and education on P/D in SCI.

Objective: Central poststroke pain (CPSP) is usually difficult to treat. Amitriptyline, the only oral preparation shown to be effective in a randomized controlled trial, is often associated with a range of side effects related to the many mechanisms of actions of tricyclic antidepressants. We investigated the effect of lamotrigine, a drug that reduces neuronal hyperexcitability, on poststroke pain., Methods: Thirty consecutive patients with CPSP (median age 59 years, range 37 to 77; median pain duration 2.0 years, range 0.3 to 12) from two centers participated in a randomized, double-blind, placebo-controlled cross-over study. The study consisted of two 8-week treatment periods separated by 2 weeks of wash-out. The primary endpoint was the median value of the mean daily pain score during the last week of treatment while treated with 200 mg/d lamotrigine. Secondary endpoints were median pain scores while on lamotrigine 25 mg/d, 50 mg/d, and 100 mg/d; a global pain score; assessment of evoked pain; areas of spontaneous pain; and allodynia/dysesthesia., Results: Lamotrigine 200 mg/d reduced the median pain score to 5, compared to 7 during placebo (p = 0.01) in the intent-to-treat population of 27 patients. No significant effect was obtained at lower doses. Twelve patients (44%) responded to the treatment. There was a uniform tendency to reduction of all secondary outcome measures, but lamotrigine only had significant effects on some of the secondary outcome measures. Lamotrigine was well tolerated with few and transient side effects. Two mild rashes occurred during lamotrigine treatment, one causing withdrawal from study., Conclusions: Oral lamotrigine 200 mg daily is a well tolerated and moderately effective treatment for central poststroke pain. Lamotrigine may be an alternative to tricyclic antidepressants in the treatment of CPSP.

Tricyclic antidepressants and anticonvulsants have become the mainstay in the treatment of pain in polyneuropathy. Within the last decade, controlled trials have shown that numerous other drugs relieve such pain. To estimate the efficacy of the different treatments, the authors identified all placebo-controlled trials and calculated numbers needed to treat (NNT) to obtain one patient with more than 50% pain relief. The NNT was 2.6 for tricyclic antidepressants, 6.7 for selective serotonin reuptake inhibitors, 2.5 for anticonvulsant sodium channel blockers, 4.1 for the anticonvulsant calcium channel blocker gabapentin, and 3.4 for the mixed opioid and monoaminergic drug tramadol, as calculated from a sufficiently large number of patients. Favorable point estimates of NNT of 1.9 for the NMDA-antagonist dextromethorphan and 3.4 for L-dopa were determined from a limited number of data. For capsaicin, the NNT calculated from many exposed patients was 5.9, but most of the data are controversial owing to trial methodology. Finally, the NNT for the antiarrhythmic sodium channel blocker mexiletine was 38, but this value may be biased because of a lack of dichotomous data in several positive trials. Tricyclic antidepressants are at the moment still the drugs of first choice, and drugs such as gabapentin, carbamazepine, and tramadol may be tried if contraindications or tolerability problems are encountered with the tricyclics.

Unlabelled: Evidence has accumulated that the N:-methyl-D-aspartate receptor system plays a role in continuous and particularly, in stimulus-evoked pain after nerve injury. We examined, in a randomized, double-blinded, cross-over fashion, the analgesic effect of memantine (a N:-methyl-D-aspartate receptor antagonist) in a group of patients with chronic pain after surgery. We randomized 19 patients to receive either memantine or placebo in the first 5-wk treatment period. A washout period of 4 wks was followed by another 5-wk treatment period with the opposite drug. The dosage of drug was increased from 5 to 20 mg/d. Pain was recorded daily, with the use of a 0-10 numeric rating scale. Before and at the end of each treatment period, pain and sensitivity were also assessed by using the McGill Pain Questionnaire, allodynia to touch, brush and cold, wind-up-like pain, and thresholds to mechanical stimuli (pressure and von Frey hair). A total of 15 patients (12 amputees and three patients with other nerve injuries) completed the study. There was no difference between memantine and placebo on any of the outcome measures. We conclude that memantine at a dosage of 20 mg/d does not reduce spontaneous or evoked pain in patients with nerve injury pain., Implications: In a randomized, double-blinded and cross-over study, the analgesic effect of memantine (a drug which reduces the excitability of sensitized neurons in the dorsal horn) was examined in 19 patients with chronic pain after nerve injury.

The present study compared capsaicin-induced muscle and skin pain in humans. Twelve healthy subjects received, in a randomised, balanced order, 3 intramuscular (i.m.) injections into the brachioradial muscle: capsaicin 100 microg/1 ml, capsaicin 100 microg/20 microl or 1 ml solvent (Tween 80), and one intradermal injection (i.d.): capsaicin 100 microg/20 microl. Local and referred pain intensities and areas were assessed from 0 to 60 min after injection. Intradermal capsaicin produced more intense local pain than i.m. capsaicin in the first min (skin: 68+/-6, muscle: 51+/-6 mm VASxmin, P<0.05). In contrast, the local pain offset was later (muscle: 38+/-5, skin: 23+/-5 min, P<0.05) and referred pain was more frequent (muscle: 9/12, skin: 1/12 subjects, P<0.01) following i.m. capsaicin compared with i.d. capsaicin. Capsaicin (1 ml) produced significantly more pain than 20 microl i.m. (pain in the first min: 1 ml: 71+/-6, 20 microl: 51+/-6 VASxmin, P<0.05, offset: 1 ml: 50+/-4, 20 microl: 38+/-5 min, P<0.05). The different local and referred pain following identical noxious stimulation of muscle and skin indicates that the neurophysiological mechanisms underlying skin and muscle pain differs. The model with identical noxious stimulation of muscle and skin may be suitable for the study of differences in deep and superficial pain as seen in the clinic.

We have attempted to examine the nerve fiber population mediating experimentally induced muscle pain in humans. Two established methods induced muscle pain: continuous, intramuscular, electrical stimulation and intramuscular infusion of hypertonic saline. A progressive nerve block was achieved by a combination of compression nerve block and intravenous regional anesthesia. Regular tests of muscle pain intensity were performed during the blocking period of 60 min. At the same time, the blocking of thick and thin afferents was monitored by assessment of proprioception and cutaneous touch, pin-prick, pressure pain, and heat-detection thresholds. Electrically induced muscle pain was inhibited (P < 0.0001) in parallel with proprioception, touch, and pin-prick, which were mediated by thick and thin myelinated nerve fibers. Saline-induced muscle pain was inhibited (P < 0.002) synchronously with heat detection and pressure pain, which are mediated by unmyelinated nerve fibers. Based on the present psychophysical experiments, it is suggested that: (1) myelinated afferents mediated mainly electrically induced muscle pain, and (2) unmyelinated afferents mediated mainly saline-induced muscle pain., (Copyright 1999 John Wiley & Sons, Inc.)

Background/aim: Severe stress results in a catabolic state with nitrogen (N) loss via hepatic urea synthesis, and in most situations a sensation of pain. Our purpose was to establish whether pain per se upregulates liver function as to urea synthesis., Methods: Ten healthy male volunteers were investigated on 3 occasions in a crossover design. Self-controlled electrical pain was applied to the abdominal skin for 30 min to an intensity of 8 on a visual analogue scale from 0 to 10. Next, the electric profile was reproduced during local analgesia (mepivacaine 2.5 mg/kg bw), and the pain was scored to only 0.5. Finally, there was a control experiment with no intervention. Alanine infusion (1 mmol/kg/h) was started 2 h before intervention and continued throughout the investigation. Urea-N synthesis rate (UNSR) was estimated hourly as urinary excretion corrected for accumulation in body water and gut hydrolysis., Results: Pain increased the Functional Hepatic Nitrogen Clearance (FHNC) assessed by the ratio UNSR/AAN (in the 3 h following pain) by 20% (22.7+/-1.2 vs 19.0+/-0.7 l/h (control), p<0.05). FHNC during local analgesia was in between (21.1+/-1.1 l/h) but not significantly different from either of the two other experiments. Mean blood amino-N concentration (AAN) and mean UNSR were comparable in the three situations. There was no difference in serum glucagon among experiments, but pain increased serum cortisol (452+/-15 vs 233+/-20 nmol/l (control), p<0.001) and plasma adrenaline (104+/-16 vs 58+/-9 pg/ml (control), p<0.05)., Conclusion: Acute, severe atraumatic pain induces an increase in the ability of the liver to convert amino- to urea-N, and thus acts as a catabolic stimulus via regulation of liver function. The measurements of known endocrine regulators of urea synthesis do not explain the phenomenon. The present data, however, suggest the hypothesis that the effects of pain were attenuated by local analgesia. If this is confirmed by further experiments, it would indicate a signal transmission to the liver which has not been previously described.

It is generally believed that opioids relieve neuropathic pain less effectively than nociceptive pain and that they have no effect on some of the key characteristics of neuropathic pain such as touch-evoked pain (allodynia). Tramadol is an analgesic drug acting directly on opioid receptors and indirectly on monoaminergic receptor systems. The aim of this trial was to determine whether tramadol relieved painful polyneuropathy and reduced allodynia. The study design was randomised, double-blind, placebo-controlled and cross-over. After baseline observations, 45 patients were assigned to one of the two treatment sequences. The dose of tramadol slow-release tablets was titrated to at least 200 mg/day and at highest 400 mg/day. During the two treatment periods of 4 weeks duration, patients rated pain, paraesthesia and touch-evoked pain by use of 0-10 point numeric rating scales. Mechanical allodynia induced by stimulation with an electronic toothbrush was rated at the end of each treatment period with a similar scale. Thirty-four patients completed the study. Their ratings for pain (median 4 vs. 6, P=0.001), paraesthesia (4 vs. 6, P=0.001) and touch-evoked pain (3 vs. 5, P<0.001) were lower on tramadol than on placebo, as were their ratings of allodynia (0 vs. 4, P=0.012). The number needed to treat to obtain one patient with >/=50% pain relief was 4.3 (95% confidence interval 2.4-20). It is concluded that tramadol appears to relieve both ongoing pain symptoms and the key neuropathic pain feature allodynia in polyneuropathy.

We have investigated the effect of pain without tissue injury on natural killer (NK) cell activity in peripheral blood in humans and the effect of local anaesthesia on the response. Ten subjects were investigated during two sessions. First, self-controlled painful electric stimulation was applied to abdominal skin for 30 min to an intensity of 8 on a visual analogue scale (0-10). Next, the electric intensity profile was reproduced during local anaesthesia (mepivacaine 10 mg ml-1 s.c. to a total dose of 2.5 mg kg-1). NK cell cytotoxicity was measured using a 4-h 51Cr-release assay against K562 target cells. NK cell activity increased from mean 22 (SEM 4)% (baseline) to 35 (6)% and 36 (5)% after 15 and 30 min of painful stimulation, respectively (P < 0.02). A simultaneous increase in the number of CD56+ cells in peripheral blood during pain was found. Stimulation after local anaesthesia did not change either NK cell activity or number. Parallel and significant increases in concentrations of plasma epinephrine and serum cortisol were observed. These changes were abolished by local anaesthesia. We conclude that acute severe pain without tissue injury markedly increased NK cell cytotoxicity. Local anaesthesia completely abolished this immunological and hormonal response.

The mechanisms underlying local and referred muscle pain are poorly understood. The aim of this experiment was to determine to which degree referred pain is dependent on peripheral or central mechanisms. This was studied by blocking sensory input from the referred pain area. Intramuscular electrical stimulation in the right anterior tibial muscle induced local muscle pain and referred pain in 12 subjects. Nerve blocks were applied on the lower limb between the local and the referred pain area for 60 min. Three different studies were performed: (1) no nerve block (2) compression block, and (3) compression block combined with intravenous regional anaesthesia. The referred pain intensity was assessed every 5 min. To monitor the blockade of myelinated and unmyelinated nerve fibres, touch, pinprick, position sense and heat and heat-pain detection thresholds were assessed on the dorsal side of the foot every 5 min. A significant reduction in referred pain intensity (40.5%) compared with the control experiment was found after 40 min with the compression ischemia nerve block until release of the tourniquet. In the combined nerve block experiment, a significant reduction of referred pain intensity (38.5%) was seen after 20 min and until the release of the tourniquet. There was no significant difference in the referred pain intensity between the two types of blocks. The present findings suggest that both peripheral and central mechanisms play a role in referred pain and that the myelinated fibres mediate the peripheral component.

Painful heterotopic stimulation (HTS) may inhibit experimental and clinical pain, an effect known as diffuse noxious inhibitory control (DNIC). This study examined the effect of painful HTS on capsaicin-induced pain intensity, brush-evoked pain intensity and area of brush-evoked pain in humans. Immersion of the foot into painful cold water significantly reduced capsaicin-induced pain intensity and brush-evoked pain intensity in the contralateral forearm, but did not change area of brush-evoked pain. The observed differential effect on the magnitude of pain and hyperalgesia on the one hand and area of hyperalgesia on the other suggests that the DNIC effect on spinal activity is selective and not general., (Copyright 1998 Elsevier Science B.V.)

The aim of the present study was to assess temporal summation within saline-induced, localized and referred muscle pain areas. The sensibility to single and repeated electrical stimuli were assessed in the muscle by means of needle electrodes and in the referred pain area by surface stimulation. The study demonstrates that temporal summation of nociceptive input from muscles exists and that the responses to single and repeated nociceptive stimuli of the referred pain area are facilitated.

The significance of preamputation pain for the development of postamputation stump and phantom pain has been discussed over the years and is still a matter of dispute. It has been argued that preamputation pain increases the risk of phantom pain and that phantom pain is a revivification of pain experienced before the amputation. The purpose of this prospective study was to clarify the relation between preamputation pain and phantom pain. Fifty-six patients scheduled for amputation of a lower limb were interviewed the day before the amputation about preamputation pain and about stump and phantom pain 1 week, 3 and 6 months after the amputation. Pain was quantitated and described using a visual analogue scale (VAS), 10 different word descriptors, the McGill Pain Questionnaire (MPQ) and the patients' own words. If phantom pain was present patients were asked if the pain was similar to any pain experienced before the amputation. At each postoperative interview patients were asked to recall preamputation pain intensity. Location of pain and analgesic requirements were registered. Preamputation pain significantly increased the incidence of stump pain (P = 0.04) and phantom pain (P = 0.04) after 1 week and the incidence of phantom pain after 3 months (P = 0.03). About 42% of the patients reported that their phantom pain resembled the pain they had experienced at the time of the amputation. However, there was no relation between the patients' own opinion about similarity between preamputation pain and phantom pain and the actual similarity found when comparing pre- and postoperative recordings of pain. Patients significantly overestimated preamputation pain intensity after 6 months.

Background: Hyperactivity of N-methyl-D-aspartate (NMDA) receptors may be one of the factors in the maintenance of postamputation stump pain., Case Report: Ketamine-a clinical available NMDA receptor antagonist-was administered intravenously to a patient with established stump pain in a double-blind saline-controlled fashion. Following infusion stump pain was alleviated for 31 hours. Ketamine reduced the allodynic area and wind-up-like pain and increased pressure-pain thresholds. Treatment was started with ketamine 50 mg x 4 per day dissolved in juice. No side effects or development of tolerance were observed during a 3-month treatment period., Conclusion: NMDA receptor antagonists may have a potential in the treatment of neuropathic pain, including stump pain.

Few clinical or experimental studies have carried out systematic investigations of cutaneous and deep sensibility in areas with referred muscle pain. Therefore, no clear signs of increased or decreased psychophysical responses to various somatosensory stimuli are found in referred pain areas. In the present study, a total of 7.1 ml 5% hypertonic saline was infused over 900 s into the m. tibialis anterior of 11 subjects. This produced local muscle pain and pain referred to the ventral aspect of the ankle. A continuous recording of the ongoing pain intensities of the local and referred pain was carried out on two electronic visual analogue scales (VAS). Before, during and 30 min after the period with referred pain, radiant heat (argon laser) stimuli, single and repeated electrical stimuli, and pressure stimuli were applied to the referred pain area. Stimulus-response (SR) functions were obtained by means of pain intensity ratings of the different stimuli at 75%, 112.5% and 150% of the individual pain threshold (PT) intensity. The pain intensities of contact heat (thermode) stimuli at 40 degrees C, 47 degrees C and 50 degrees C and pin-prick stimuli with von Frey hair were also assessed in the referred pain area. The saline-induced local muscle pain intensity was higher than the intensity of the referred pain (P < 0.05). The referred pain intensity was significantly higher in the 20-460 s interval than in the 460-900 s interval (P < 0.05). This difference was not seen for the local muscle pain. During the period with referred pain, significantly decreased responses to radiant heat and pressure stimuli were found at 112.5% and 150% of PT intensity (P < 0.05). Further, significantly increased responses to single and repeated electrical stimuli at 75% and 112.5% of PT intensity (P < 0.05) were also found. After the period with referred pain, a considerably decreased response to single and repeated, electrical stimuli (P < 0.05) was present together with significantly increased responses to contact heat stimuli at 40 degrees C and radiant heat stimuli at 75% of PT intensity (P < 0.05). The present results suggest that ongoing muscle pain can cause modality-specific (and bi-directional) sensory changes in the referred pain area. This could explain why previous studies have reported both decreased and increased responses in referred pain areas.

Intramuscular injection of hypertonic saline is a good model to study human muscle pain (Kellgren 1938). The present study concerns the intramuscular (i.m.) pain mediators in saline-induced muscle pain. In experiment 1, the diffusion of infused hypertonic and isotonic saline (0.5 ml) in m. tibialis anterior was illustrated by magnetic resonance imaging (MRI) in one subject. In experiment 2, six volunteers received four sequential infusions (0.5 ml given at 5 min intervals) of isotonic saline and thereafter four sequential infusions (0.5 ml given at 5 min intervals) of hypertonic saline into m. tibialis anterior. The isotonic and hypertonic saline infusions were computer-controlled and separated by 20 min. The muscle pain intensity was assessed by continuous recordings on a visual analogue scale (VAS). One microdialysis probe was inserted 1 cm from the infusion needle in m. tibialis anterior and another probe in the other m. tibialis anterior. Concentrations of the i.m. sodium, potassium, magnesium, and prostaglandin E2 (PGE2) were assessed from the dialysates. Intramuscular electromyography (EMG) and pressure were assessed in the area of the infused saline. In experiment 1, the infusion of hypertonic and isotonic saline created a visible saline-pool on the MRI scans. These saline-pool volumes were stable and not correlated to the pain scores. In experiment 2, infusion of isotonic saline produced little pain compared to infusion of hypertonic saline. Maximal pain was reported after the first infusion of hypertonic saline and thereafter the pain gradually decreased with subsequent infusions of hypertonic saline. During infusion of hypertonic saline the i.m. sodium and potassium concentrations increased significantly, i.m. magnesium concentration tended to be increased, and the i.m. PGE2 concentration tended to be decreased although these changes were not significant. The i.m. EMG was smaller during and after infusions of hypertonic saline compared with isotonic saline. The i.m. pressure was not different during the infusions of hypertonic and isotonic saline but was increased between the infusions of hypertonic saline. This study has shown that i.m. infusion of hypertonic saline produced a saline-pool, causing the i.m. pressure to increase. Possibly, pain activation and cessation are related to increased intramuscular sodium and potassium content respectively.

Systemically administered opioids produce a profound inhibition of noxious-evoked activity peripherally, spinally and supraspinally in several species, including man. The role of the brain in opioid mediated-pain control has been less well characterized than that occurring at lower levels in the nervous system. Yet, classical studies indicate that in morphine-induced analgesia the individual senses noxious stimuli, but the affective, motivational and aversive character of the stimulus is no longer present. This observation indicates that morphine probably exerts a specific action on those brain systems that control complex behaviors like aversion and motivation. The failure to document such effects in experimental studies may in part be explained by less suitable methods for assessing antinociception, e.g. measurements of simple reflex behaviors. Experimental animal studies show that supraspinal opioids may influence nociception by several distinct mechanisms, which differ from those seen in the spinal cord: Change of activity in descending bulbospinal pathways. Direct inhibition of noxious throughput at brainstem level. Indirect inhibition of noxious responding brainstem neurons projecting to supraspinal centers. Influence ascending forebrain systems. Direct cortical or thalamic inhibition. In humans, the antinociceptive actions of opioids occurring in the brain has until recently been like looking into a "black box". The introduction of new imaging techniques may provide new tools for directly measuring the antinociceptive action of opioids in the brain under normal and pathological conditions. In particular, the emotional-affective aspect of pain and how this is modulated by opioids will be of interest to study.

In this experimental study brief/prolonged and single/repeated, nociceptive stimuli (laser, thermode and electrical) were used to investigate sensory changes in capsaicin-induced primary and secondary hyperalgesia. The pain threshold to prolonged thermode stimulation was reduced in the primary area and remained constant in the secondary area. The pain thresholds to brief laser and electrical stimuli remained constant in the primary but reduced in the secondary area. The summation pain threshold to repeated (five stimuli delivered at 0.5, 1, 2 and 3 Hz) laser and electrical stimuli was reduced in the secondary area. The stimulus response functions to single laser and electrical stimuli were increased in the secondary area.

Ten patients (4 female, 6 male) aged 34-67 years suffering from peripheral neuropathic pain participated in a double-blind placebo-controlled study where ketamine or magnesium chloride were administered by a 10 min bolus infusion (ketamine: 0.84 mumol/kg = 0.2 mg/kg, magnesium: 0.16 mmol/kg) followed by a continuous infusion (ketamine: 1.3 mumol/kg/h = 0.3 mg/kg/h, magnesium: 0.16 mmol/kg/h). Ongoing pain determined by VAS score, area of touch-evoked allodynia, detection and pain thresholds to mechanical and thermal stimuli were measured before and during drug infusion. Ketamine produced a significant reduction of spontaneous pain (57%) and of the area of allodynia (33%). Magnesium chloride reduced pain (29%) and area of allodynia (18%) insignificantly. Following ketamine there was a significant correlation between the reduction in ongoing pain and reduction in area of touch-evoked allodynia. Detection and pain thresholds to mechanical and thermal stimuli were not significantly changed by the drugs. These findings suggest that both ongoing pain and touch-evoked pain (allodynia) in neuropathic pain are inter-related phenomena, which may be mediated by the same mechanism and involving a N-methyl-D-aspartate receptor.

Vertex potentials evoked by painful and non-painful electrical skin stimuli were recorded in 10 healthy male volunteers. Peak-to-peak amplitudes of the major vertex potential components were compared with subjective rating of the stimuli. While a significant correlation was observed between peak-to-peak amplitudes and stimulus rating following non-painful stimuli, generally no such correlation was present following stimulations above the pain threshold. These findings suggest that vertex potentials elicited by electrical skin stimuli may reflect central processing of non-noxious afferent information rather than of pain-related information.

Rats were stereotaxically implanted with microinjection cannulae aimed at sites ranging caudally from the lower medulla and rostrally to the diencephalon and received microinjections of the excitatory amino acid: L-glutamate 30 nmol/0.5 microliters. The subsequent spontaneous behavioral response and the effect on the thermal noxious-evoked tail flick (TF) and hot plate (HP) responses was recorded. From 331 brain sites mapped with glutamate, an elevation of tail flick and hot plate response latencies was observed in 59 cases and in 34 of these sites the antinociceptive activity was preceded by a shortlasting aversion characterized by vocalization and running. The glutamate-sensitive sites at which TF and HP response latencies were elevated were exclusively distributed in the medullary reticular formation (MRF) and the mesencephalic periaqueductal gray matter (PAG). The aversive and antinociceptive activity of glutamate was dose-dependent and mimicked by the excitatory amino acid (EAA) receptor agonists N-methyl-D-aspartate + (NMDA) kainate and less so quisqualate. The EAA receptor antagonists MK-801 and AP-5, but not glutamyl-amino-methyl-sulfonic acid, antagonized in a dose-dependent fashion both the aversive and antinociceptive responses evoked from the PAG. It is suggested that NMDA receptor-linked neurons in the PAG activate both nociceptive and antinociceptive systems.

In awake, freely moving rats, the intracerebral administration of the excitatory amino acid L-glutamate (30 nmol/0.5 microliters) into discrete regions of the brainstem resulted in a transient and spontaneous pain-like syndrome characterized by an initial vocalization and vigorous escape behavior. Systematic microinjection mapping studies were carried out at sites distributed caudally from the lower medulla and rostrally into diencephalon. These studies revealed that the spontaneous pain-like behavior was observed to occur after glutamate injection in 13% of 331 microinjected sites, and these sensitive sites were largely limited to the mesencephalic periaqueductal gray matter. The behavioral syndrome was dose-dependent and antagonized in a dose-dependent fashion by the glutamate receptor antagonists MK 801 and DL-2-amino-5 phosphonovalerate but not by gamma-D-glutamyl-amino-methylsulfonic acid. The pain-like behavior was also produced by the other excitatory amino acid receptor agonists N-methyl-D-aspartate, quisqualate and to a certain extent by kainate in a dose-dependent manner with the order of potency being N-methyl-D-aspartate = kainate greater than quisqualate greater than D-glutamate. The effects of N-methyl-D-aspartate and quisqualate were antagonized by MK 801 and DL-2-amino-5 phosphonovalerate but not by gamma-D-glutamyl-amino-methylsulfonic acid. It is suggested that the pain-like behavioral syndrome is the result of focal occupation of N-methyl-D-aspartate receptors on neuronal populations in the terminal regions of rostrally projecting spinomesencephalic systems.

In addition to the well known paraplegia or tetraplegia, lesions of the spinal cord frequently cause a series of disturbances of sensation in the segments around or distal to the lesion. Disturbances of sensation in spinal cord lesions are painful or non-painful. The painful and also the non-painful sensations may represent irritative and withdrawal phenomena. A series of central neurogenic pains seem to be best explained by spontaneous neuronal activity in sensory spinal cord neurones which have lost the peripheral, segmental and descending neuronal control from the nervous system. Surgical treatment of pain in cases of spinal cord lesions is rarely considered apart from root-avulsion where surgical lesion in the superficial part of the posterior horn is effective. No specific treatment is as yet available for pain and disturbances of sensation in cases of spinal cord injury. However, on the basis of our limited knowledge of the pathogenesis of these symptoms, future therapeutic strategy will be directed towards not only the peripheral but also the central points of attack. Treatment of painful conditions in patients with spinal cord injuries, as in other states of chronic pain, should also include social and psychological support.

In rats, microinjection of the opioid agonist morphine (15-45 nmol/0.5 microliter) and the excitatory amino acid monosodium glutamate (30-60 nmol/0.5 microliter) into identical brainstem sites within the mesencephalic periaqueductal gray matter (PAG; 23 sites) and the rostral ventromedial medulla (RVM; 22 sites) produced an increase of tail flick and hot plate response latencies. At both PAG and RVM sites, there was a statistically significant relationship between the effect obtained with morphine and with glutamate on the two nociceptive responses. While morphine and glutamate produced indistinguishable inhibition of tail flick and hot plate response latencies in the PAG, the tail flick inhibition following RVM morphine, but not RVM glutamate, displayed a clear plateau. One parsimonious interpretation of these data is that (1) glutamate directly increases the activity in the bulbospinal pathway, and (2) morphine inhibits an evoked or tonic suppression of a bulbospinal projection.

Spinal rats and rats with an intact neuraxis given the dopamine (DA) agonist R-apomorphine (0.31-1.75 mumol/kg) in the lumbar subarachnoid space by intrathecal injection were tested 5 and 10 min later for spinal analgesia (increased tail-flick response latency). Apomorphine produced analgesia in spinal rats but not in rats with an intact neuraxis. However, pretreatment of intact rats with the serotonergic (5-HT) receptor antagonist methysergide, the noradrenergic (NA) receptor antagonist phentolamine or the two antagonists together led to a dose-dependent analgesia following apomorphine. Intact rats pretreated with the monoamine depleting drug reserpine, the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) or the NA synthesis inhibitor FLA 63 also showed analgesia to apomorphine. On the other hand, pretreatment with the catecholamine depleting agent alpha-methyl-p-tyrosine (AMPT), the beta-adrenergic receptor blocker propranolol or the opioid receptor antagonist naloxone failed to produce DA analgesia. The present findings suggest that both 5-HT and NA descending fiber systems exert tonic inhibitory effects on spinal DA nociceptive processes.

In 10 cancer patients with cutaneous allodynia, intravenous lidocaine (5 mg/kg body weight) or 0.9% NaCl was given in a double blind, cross-over study to determine the analgesic effect. One patient had complete and one had partial pain relief with lidocaine infusion, whereas three patients experienced partial pain relief with placebo. Neither lidocaine nor placebo reduced pain intensity or consumption of analgesics significantly during the study period. Intravenous infusion of lidocaine cannot be recommended as routine pain treatment in cancer patients with cutaneous allodynia or pain, but further studies are needed to test the effect of lidocaine on different peripheral stimuli.

D-Ala2-D-Leu5-enkephalin (DADL) along with dimers formed from tetra(DTE: des-Leu5-enkephalin)- or pentapeptide (DPE: Leu5-enkephalin) coupled by methylene bridges of various lengths (n) have been shown in in vitro systems to possess varying degrees of mu/delta-receptor selectivity. In the present studies we have systematically compared the intrathecal effect of these agents and morphine on the cutaneous stimuli (hot plate (HP) and tail flick (TF) and visceral-chemical (writhing) tests in the rat. The following observations were made. (1) Dimers with high delta-receptor selectivity were active in the TF(DPE2 greater than or equal to DADL greater than or equal to DTE2 greater than or equal to morphine greater than DPE12 much greater than DTE12 = 0) and HP(DPE2 greater than or equal to DTE2 greater than or equal to DADL greater than or equal to morphine greater than DPE12 greater than or equal to DTE12 greater than 0. To examine cross-tolerance, the intrathecal ED50 for morphine, DPE and DADL were determined in rats rendered tolerant by subcutaneous morphine pellets. The TF ED50 tolerant/TF ED50 naive was 18.4, 5.4 and 1.3, respectively. The ratio of activity on the HP was 14.0, 4.7 and 2.2 (2) On the visceral-chemical test, only morphine was active. The dimers or DADL in doses which totally blocked the TF or HP are at higher doses which were just below those producing motor dysfunction had no effect on the writhing response. (3) At high intrathecal doses (40 X TF ED50), morphine produced a motor rigidity which blocked the placing and stepping reflex.(ABSTRACT TRUNCATED AT 250 WORDS)

The latency of the tail-flick, following intrathecal infusion of the dopamine (DA) agonist, R-apomorphine was measured in rats with intact spinal cord or with spinal cord lesions. Apomorphine failed to influence the tail-flick response in intact rats, whereas it elevated the latency of the tail-flick in rats with either total spinal cord transection, or bilateral lesions of the dorsolateral funiculi (DLF), but not in rats with lesions in either the dorsal columns or the medioventral parts of the lateral funiculi. The findings suggest that pathways in the dorsolateral funiculi modulate DA-mediated sensory processes and possible mechanisms are discussed.

Rats were used to determine whether stress-induced analgesia (SIA) can be produced by conditioning with interoceptive stimuli (LiCl) as with exteroceptive stimuli (footshock). SIA was measured using a tail-flick test. As expected, unavoidable footshock as well as conditioning with footshock produced SIA. In contrast, conditioning with LiCl failed to cause SIA. The findings support the notion of functional differences in neural substrates for conditioning by exteroceptive and interoceptive cue.

The administration of the excitatory amino acid glutamate into the periaqueductal gray (PAG) or ventromedial medulla (VM) resulted in a reliable, short lasting elevation in the tail flick and hot plate response latencies in rats. The prior intrathecal administration of methysergide (30 micrograms) or phentolamine (30 micrograms) into the lumbar space produced a significant antagonism of the elevated tail flick reflex latencies evoked by glutamate given into the PAG and VM. Intrathecal naloxone (10 micrograms) significantly antagonized the effects on tail flick produced by VM, but not PAG, injections of glutamate. No intrathecal treatment significantly antagonized the effects of intracerebral glutamate on the supraspinally organized hot plate response. These results indicate that the excitation of glutamate-receptor linked systems in the PAG and VM exert a powerful antireflexive effect on spinal processing by the activation of spinopetal monoamine pathways, but that their mechanisms do not totally overlap as the VM systems also directly or indirectly activate a naloxone sensitive link in the spinal cord. The failure to antagonize the supraspinally organized hot plate response by intrathecal antagonists indicates that aside from an effect (if any) on spinal sensory processing, these brainstem systems may also act at the supraspinal level to actively modulate the animal's response to an otherwise aversive somatic stimulus.