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Endomorphin-2, a newly discovered endogenous opioid peptide and agonist at the mu-opioid receptor, was injected intrathecally in normal rats and animals with unilateral peripheral inflammation or sciatic nerve section and its effect on the nociceptive flexor reflex was analysed. In normal rats, intrathecal endomorphin-2 induced a strong and dose-dependent depression of the reflex, which was naloxone-reversible. The effect of intrathecal endomorphin-2 was fairly brief, lasting for about 20-30 min at the highest dose, 4 microg. The effect of endomorphin-2 in inflamed rats was not significantly different from that in normals. After nerve section some rats developed autotomy behavior. In these rats endomorphin-2 had significantly reduced effect. However, the reflex depressive effect of intrathecal endomorphin-2 was unchanged in axotomized rats without autotomy. It is suggested that intrathecal endomorphin-2 has antinociceptive effect in the rat spinal cord under normal and inflammatory conditions. After peripheral nerve injury the sensitivity to endmorphin-2 may be reduced in rats that exhibit ongoing neuropathic pain-like behaviors.

We performed resection of part of an injured peripheral nerve in 20 patients with post-traumatic neuralgia, after conservative treatment had failed. All had burning pain, paraesthesia and dysaesthesia in the area innervated by the injured nerve. We resected the nerve in the area in which the patient felt pain, and a further 3 cm proximal to the site of injury. In all cases, the local pain disappeared or markedly decreased. The areas of pain relief and of nerve resection coincided completely in 17 patients and partially in three. The results were assessed as excellent by five patients, good by 11, and fair by four. There were no poor results. Histological examination of the resected nerves showed Wallerian degeneration and immunohistochemical tests indicated that substance P, a polypeptide which may contribute to nociceptive transmission, was present in the tissue around the degenerated nerves.

Pain, particularly chronic pain, arises from the interaction of multiple simultaneously operating physiologic processes. The current understanding of the anatomy and physiology of pain is limited to a characterization of pathways and does not explain why a particular stimulus is felt as pain of a particular kind and intensity. In this article, we trace the afferent pain pathways from periphery (reception) to center (perception), i.e., from peripheral nerve, through the spinal cord and brain stem, to the thalamus and cerebral cortex. A number of neurosurgical procedures for the treatment of pain are discussed, and their anatomic basis is explained.

We obtained intervertebral discs with cartilage endplates and underlying cancellous bone at operation from patients with degenerative disc disease and then used immunohistochemical techniques to localise the nerves and nerve endings in the specimens. We used antibodies for the ubiquitous neuronal protein gene product 9.5 (PGP 9.5). Immunoreactivity to neuropeptide Y was used to identify autonomic nerves and calcitonin gene-related peptide (CGRP) and substance P to identify sensory nerves. Blood vessels were identified by immunoreactivity with platelet-endothelial cell-adhesion molecule (CD31; PECAM). In a control group with no known history of chronic back pain, nerve fibres immunoreactive to PGP 9.5 and neuropeptide Y were most closely related to blood vessels, with occasional substance P and CGRP immunoreactivity. In patients with severe back pain and markedly reduced disc height, proliferation of blood vessels and accompanying nerve fibres was observed in the endplate region and underlying vertebral bodies. Many of these nerves were immunoreactive to substance P or CGRP, and in addition, substance P- and CGRP-immunoreactive nociceptors were seen unrelated to blood vessels. Quantification by image analysis showed a marked increase in CGRP-containing sensory nerve fibres compared with normal control subjects. We speculate that a chemotactic response to products of disc breakdown is responsible for the proliferation of vascularity and CGRP-containing sensory nerves found in the endplate region and vertebral body adjacent to degenerate discs. The neuropeptides substance P and CGRP have potent vasodilatory as well as pain-transmitting effects. The increase in sensory nerve endings suggests increase in blood flow, perhaps as an attempt to augment the nutrition of the degenerate disc. The increase in the density of sensory nerves, and the presence of endplate cartilage defects, strongly suggest that the endplates and vertebral bodies are sources of pain; this may explain the severe pain on movement experienced by some patients with degenerative disc disease.

It has been suggested that the unmyelinated small diameter afferent nociceptive C-fibres are impaired in diabetes mellitus. We have recently demonstrated that these fibres are the prerequisite for neurogenic inflammation induced by mechanical or chemical irritations. These experiments were designed to characterize the neurogenic inflammatory responses of gingivomucosal tissue in the early phase of experimental induced diabetes mellitus in rat. Effect of dental ligature on the gingivomucosal (GM) vascular permeability was studied in control rats and in rats pretreated with streptozotocin at d 7 and 14 following streptozotocin administration. In separate groups of control and streptozotocin diabetic rats studies were also performed to investigate the effect of local capsaicin application on GM vascular permeability on d 14. Vascular permeability was assessed by means of Evans blue extravasation. The ligature placed around the mandibular left first molar caused a significant increase vascular permeability of GM tissue on the ipsilateral side on both d 7 and 14 after the ligation in control rats. In streptozotocin diabetic rats on d 7, there was also a significant elevation of Evans blue extravasation in the tissue tested on the ligature side. However, on d 14 the ligation failed to produce any changes in Evans blue extravasation on the ipsilateral side, i.e. no difference in GM vascular permeability could be recorded between the two sides in streptozotocin diabetic rats. Topical capsaicin administration produced significant Evans blue extravasation in GM tissue of control rats compared to that observed in diabetic rats on d 14 after streptozotocin treatment. Electron microscopic and light microscopic studies demonstrated fibre degeneration of the C neurones and less inflammatory cells in streptozotocin-induced diabetes in the gingivomucosal tissue. These findings appear to indicate that the inflammatory responses induced by mechanical (dental ligature) and/or chemical irritants (topical application of capsaicin) in the gingivomucosal tissue are altered in streptozotocin diabetic rats and this alteration is due to the diabetes-induced damage to the unmyelinated C fibres.

A recent positron emission tomography (PET) study demonstrated that the anterior cingulate cortex (area 24), in addition to SI and SII cortices, was activated by painful stimuli. In order to elucidate the participation of relay nuclei in the ascending pain pathway to area 24, we performed a regrograde labelling study with WGA-HRP injection into area 24 in cats. Area 24 was found to receive pain-related thalamic inputs from the intralaminar nuclei including the central medial nucleus, midline nuclei, modiodorsal nucleus and possibly the submedial nucleus. We then examined the expression of Fos protein in CNS induced by formalin injection into the face in cats. Fos positive neurons were demonstrated in areas 23 and 24, the anterior limbic area, insular cortex, midline and paraventricular nuclei in the thalamus, paraventricular nucleus and other areas in the hypothalamus, and in many nuclei in the brainstem in both the formalin-injected group and the control group (anesthesia only). Labelled regions appeared to correspond to stress-related sites. The sole difference from the control group was the expression of Fos in the coronal gyrus and in the trigeminal caudalis nucleus in the experimental group. Although more Fos positive cells were observed in area 24 in experimental than in control cats, the difference was not significant. Our findings suggest that the demonstrated response of area 24 on PET scan represents stress- and emotion-related events rather than pain. Surgical intervention into the anterior cingulate cortex including cingulotomy thus appears to relieve stress and emotion associated with chronic pain, but not pain itself.

A large kinship is reported with dominantly inherited spastic paraplegia starting in the first decade of life; its clinical evolution was indistinguishable from that of "pure" hereditary spastic paraplegia (HSP). However, all patients studied had electrophysiological evidence of a predominantly sensory polyneuropathy, which was confirmed on nerve biopsy in three. The histological findings indicated virtually complete loss of large diameter fibres with relative preservation of small myelinated and non-myelinated fibres. The neuropathy was largely asymptomatic and there were no trophic ulcers. This family represents a distinct entity which differs from other reported cases of HSP with neuropathy by virtue of the clinical predominance of the pyramidal syndrome, the greater impairment of large fibre sensory modalities than of pain or temperature modalities, and the consequent absence of mutilation.

To confirm the innervation of the anterior cruciate ligament and anterior cruciate allograft the anterior cruciate ligament was grafted allogenic and deep-freeze preserved, in 12 white New Zealand rabbits. After removal from the donor animal the ligaments and pertaining bone tissue were placed in deep freeze at -90 degrees C for 72 hours. The grafts were fixed in the receiving animal by means of transosseous wire sutures. The non-operated contralateral anterior cruciate ligament served as control. Follow-up examinations were performed after 3, 6, 12, 24, 36 and 52 weeks. Immunohistochemical methods were employed to examine newly ingrown nerve fibres. Monoclonal antibodies against neurofilaments (to identify rapid conducting mechanoreceptive afferent A fibres) were used, as well as substance P (to identify slow conducting nociceptive afferent C fibres) and thyrosine hydroxylase (for the identification of vasomotor efferent C fibres). In the control ligaments we found an abundant amount of nerve fibres of all three kinds, each of these having its own typical distribution pattern. The fibres were mainly subsynovial, in some cases however also localised in the interfascicular connective tissue septae. At specialised end organs we could only identify Ruffini's corpuscles. No nerve fibres were found in the cruciate ligament allografts after 3 weeks, but an initial few fibres showed up after 6 weeks. After 12 weeks individual nerve fibres of all 3 kinds became noticeable, and after 24 weeks all three kinds of fibres were abundantly represented. No specialised end organs were found in the allografts.(ABSTRACT TRUNCATED AT 250 WORDS)

Pain is a common experience of the ICU patient, with a diverse clinical manifestation. To manage pain we must understand its anatomic pathways and physiology. This article reviews the development of our understanding of the theory of pain from Descartes to the gate theory of Melzack and Wall. We will review the anatomy of the pathways of pain and the interrelationship of "A" and "C" fibers and the unique nature of the opiate receptor.

If applied locally around a peripheral sensory nerve, Formyl-Leurosin, a semi-synthetic diindol alkaloid of Vinca rosea--that, just like other mitotic spindle inhibitors, induces blockade of axoplasmic transport via inhibiting microtubular function--causes transganglionic degenerative atrophy of central terminals of primary nociceptive neurons in the substantia gelatinosa Rolandi of the spinal cord. In contrast, if applied to dorsal roots, Formyl-Leurosin fails to induce such alterations. Based upon these observations it is postulated that blockade of retrograde axoplasmic transport, rather than that of the orthograde one, is the decisive factor in the pathomechanism of transganglionic degenerative atrophy.