Catherine M. Cahill

Neuropathic pain: a practical guide for the clinician

Neuropathic pain, caused by various central and peripheral nerve disorders, is especially problematic because of its severity, chronicity and resistance to simple analgesics. The condition affects 2%–3% of the population, is costly to the health care system and is personally devastating to the people who experience it. The diagnosis of neuropathic pain is based primarily on history (e.g., underlying disorder and distinct pain qualities) and the findings on physical examination (e.g., pattern of sensory disturbance); however, several tests may sometimes be helpful. Important pathophysiologic mechanisms include sodium-and calcium-channel upregulation, spinal hyperexcitability, descending facilitation and aberrant sympathetic–somatic nervous system interactions. Treatments are generally palliative and include conservative nonpharmacologic therapies, drugs and more invasive interventions (e.g., spinal cord stimulation). Individualizing treatment requires consideration of the functional impact of the neuropathic pain (e.g., depression, disability) as well as ongoing evaluation, patient education, reassurance and specialty referral. We propose a primary care algorithm for treatments with the most favourable risk–benefit profile, including topical lidocaine, gabapentin, pregabalin, tricyclic antidepressants, mixed serotonin–norepinephrine reuptake inhibitors, tramadol and opioids. The field of neuropathic pain research and treatment is in the early stages of development, with many unmet goals. In coming years, several advances are expected in the basic and clinical sciences of neuropathic pain, which will provide new and improved therapies for patients who continue to experience this disabling condition.

Up-regulation and trafficking of δ opioid receptor in a model of chronic inflammation: implications for pain control

&NA; Pharmacological and physiological evidence supports a role for delta (&dgr;) opioid receptors in the nociceptive mechanisms of inflammation. However, few data exist regarding &dgr; opioid receptor expression and localization in such conditions. In this study, we have assessed the distribution and function of &dgr; opioid receptors in the rat spinal cord following induction of chronic inflammation by intraplantar injection of complete Freunds adjuvant (CFA). Intrathecal administration of the selective &dgr; opioid receptor agonist, d‐[Ala2, Glu4] deltorphin, dose‐dependently reversed thermal hyperalgesia induced by CFA. In situ hybridization and Western blotting experiments revealed an increase in &dgr; opioid receptor mRNA and protein levels, respectively, in the dorsal lumbar spinal cord ipsilateral to the CFA injection site compared to the contralateral side and sham‐injected controls. By electron microscopy, immunopositive &dgr; opioid receptors were evident in neuronal perikarya, dendrites, unmyelinated axons and axon terminals. Quantification of immunopositive signal in dendrites revealed a twofold increase in the number of immunogold particles in the ipsilateral dorsal spinal cord of CFA‐injected rats compared to the contralateral side and to sham‐injected rats. Moreover, the relative frequency of immunogold particles associated with or in close proximity to the plasma membrane was increased in the ipsilateral dorsal spinal cord, indicating a more efficient targeting of &dgr; opioid receptors to neuronal plasma membranes. These data demonstrate that CFA induces an up‐regulation and increased membrane targeting of &dgr; opioid receptors in the dorsal spinal cord which may account for the enhanced antinociceptive effects of &dgr; opioid receptor agonists in chronic inflammatory pain models.

Immunohistochemical distribution of delta opioid receptors in the rat central nervous system : evidence for somatodendritic labeling and antigen-specific cellular compartmentalization

Many studies have reported on the distribution of delta opioid receptors (δOR) in the mammalian central nervous system (CNS) by using a variety of techniques. However, no general consensus has emerged with regards to the localization of this receptor due to inconsistencies in the immunohistochemical literature. In the present study, we analyzed the cellular and subcellular distribution of immunoreactive δOR in the rat CNS using two different antibodies (directed against a sequence in the C‐terminus or N‐terminus of the rat δOR). By using Western blotting, these two antibodies recognized similar forms of the δOR in COS‐7 cells transfected with this receptor, but distinct forms in membranes from the rat spinal cord. By using light microscopic immunohistochemistry, both antibodies recognized identical populations of nerve cell bodies throughout the CNS; the distribution of these cell bodies conformed to that of δOR mRNA‐expressing cells detected by in situ hybridization. However, whereas the C‐terminus‐directed antibody recognized predominantly perikarya and proximal dendrites, the N‐terminus–directed antibody also labeled extensively dendritic and terminal arbors. Furthermore, by using electron microscopy, the two antibodies were found not only to label differentially somatodendritic versus axonal compartments, but also plasma membrane versus cytoplasmic ones, suggesting that distinct immunological forms of the receptor are being targeted preferentially to different cellular and subcellular domains. J. Comp. Neurol. 440:65–84, 2001.

Anti-allodynic effects of peripheral delta opioid receptors in neuropathic pain

Abstract The analgesic effects of local administration of opioid agonists into peripheral tissues in alleviating pain have been well documented in both clinical and preclinical studies, although few studies have examined their effects in neuropathic pain. In this study, we investigated the anti‐allodynic effects of peripherally acting delta opioid receptor (DOR) agonists in a rat model of neuropathic pain. Peripheral nerve injury (PNI) produced a time‐dependent decrease in mechanical withdrawal thresholds that was attenuated by local administration into the hind paw of either morphine or the DOR agonist deltorphin II. Using Western blotting techniques, no change in DOR protein expression was detected in DRG ipsilateral to the site of injury compared to contralateral. However, an up‐regulation of DOR protein was found in neuropathic DRG compared to sham, suggesting that there may be a bilateral increase in the expression of DOR following PNI. Results obtained from immunohistochemical studies confirmed up‐regulation in small and large DRG neurons in neuropathic compared to sham animals. Additionally, there was an increase in DOR protein within the ipsilateral sciatic nerve of neuropathic animals compared to sham and contralateral neuropathic conditions indicating the occurrence of receptor trafficking to the site of injury. Taken together, our findings suggest that functional peripheral DORs are present in sensory neurons following PNI and validate the development of selective DOR agonists for alleviating neuropathic pain.

Morphine-Induced Changes in δ Opioid Receptor Trafficking Are Linked to Somatosensory Processing in the Rat Spinal Cord

An in vivo fluorescent deltorphin (Fluo-DLT) internalization assay was used to assess the distribution and regulation of pharmacologically available δ opioid receptors (δORs) in the rat lumbar (L4-5) spinal cord. Under basal conditions, intrathecal injection of Fluo-DLT resulted in the labeling of numerous δOR-internalizing neurons throughout dorsal and ventral horns. The distribution and number of Fluo-DLT-labeled perikaryal profiles were consistent with that of δOR-expressing neurons, as revealed by in situ hybridization and immunohistochemistry, suggesting that a large proportion of these cells was responsive to intrathecally administered δOR agonists. Pretreatment of rats with morphine for 48 hr resulted in a selective increase in Fluo-DLT-labeled perikaryal profiles within the dorsal horn. These changes were not accompanied by corresponding augmentations in either δOR mRNA or 125I-deltorphin-II binding levels, suggesting that they were attributable to higher densities of cell surface δOR available for internalization rather than to enhanced production of the receptor. Unilateral dorsal rhizotomy also resulted in increased Fluo-DLT internalization in the ipsilateral dorsal horn when compared with the side contralateral to the deafferentation or to non-deafferented controls, suggesting that δOR trafficking in dorsal horn neurons may be regulated by afferent inputs. Furthermore, morphine treatment no longer increased Fluo-DLT internalization on either side of the spinal cord after unilateral dorsal rhizotomy, indicating that μOR-induced changes in the cell surface availability of δOR depend on the integrity of primary afferent inputs. Together, these results suggest that regulation of δOR responsiveness through μOR activation in this region is linked to somatosensory information processing.

Chronobiological characteristics of painful diabetic neuropathy and postherpetic neuralgia: diurnal pain variation and effects of analgesic therapy.

Abstract Clinical impressions suggest that neuropathic pain is often worse at night and significantly impairs sleep. However, the temporal pattern of neuropathic pain during waking hours has not been clearly characterized. Using clinical trial data, we have evaluated the diurnal variation of pain intensity before and during analgesic treatment in patients with diabetic neuropathy (DN) and postherpetic neuralgia (PHN). Pain intensity (0–10) measures throughout the day from a placebo‐controlled trial of around‐the‐clock administration of gabapentin, morphine and a gabapentin–morphine combination in neuropathic pain patients were examined. Baseline data in untreated patients revealed no effect of day of week but a significant effect of time of day in both DN (P<0.001) and PHN (P<0.001) such that pain intensity progressively increases throughout the day. This temporal pattern is essentially preserved during treatment with gabapentin, morphine and their combination. Neuropathic pain intensity progressively increases throughout the day and this temporal profile appears to be unaffected by treatment with gabapentin and/or morphine. Advancing our understanding of the chronobiology of neuropathic pain may shed new light on various neurohormonal and neurophysiologic influences and lead to the identification of novel therapeutic targets. Furthermore, recognizing diurnal pain patterns may guide treatment strategies such as the targeted timing of analgesic therapies.

Spatial normalization, bulk motion correction and coregistration for functional magnetic resonance imaging of the human cervical spinal cord and brainstem

Functional magnetic resonance imaging (fMRI) of the cortex is a powerful tool for neuroscience research, and its use has been extended into the brainstem and spinal cord as well. However, there are significant technical challenges with extrapolating the developments that have been achieved in the cortex to their use in the brainstem and spinal cord. Here, we develop a normalized coordinate system for the cervical spinal cord and brainstem, demonstrating a semiautomated method for spatially normalizing and coregistering fMRI data from these regions. fMRI data from 24 experiments in eight volunteers are normalized and combined to create the first anatomical reference volume, and based on this volume, we define a standardized region-of-interest (ROI) mask, as well as a map of 52 anatomical regions, which can be applied automatically to fMRI results. The normalization is demonstrated to have an accuracy of less than 2 mm in 93% of anatomical test points. The reverse of the normalization procedure is also demonstrated for automatic alignment of the standardized ROI mask and region-label map with fMRI data in its original (unnormalized) format. A reliable method for spatially normalizing fMRI data is essential for analyses of group data and for assessing the effects of spinal cord injury or disease on an individual basis by comparing with results from healthy subjects.

Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain.

&NA; Previous studies from our laboratory have demonstrated that both chronic inflammatory pain, induced by intraplantar injection of complete Freunds adjuvant (CFA), and prolonged (48 h) stimulation of mu‐opioid receptors (&mgr;OR) by systemic administration of a variety of selective agonists, resulted in enhanced plasma membrane targeting of delta‐opioid receptors (&dgr;OR) in neurons of the dorsal spinal cord. To determine whether &dgr;OR trafficking induced by chronic inflammation was dependent on the activation of &mgr;OR, we investigated by immunogold cytochemistry the effects of intraplantar CFA injection on the plasma membrane density of &dgr;OR in &mgr;OR knockout (KO) mice. In untreated wild‐type (WT) mice, only a small proportion of &dgr;OR was associated with neuronal plasma membranes in the dorsal horn of the spinal cord. The CFA‐induced inflammation produced a significantly higher ratio of plasma membrane to intracellular receptors, as well as a 75% increase in the membrane density of immunoreactive &dgr;OR, in dendrites of the ipsilateral dorsal horn as compared to untreated mice. This increase in the membrane density of &dgr;OR was likely due to a recruitment of receptors from intracellular stores since no difference in the overall &dgr;OR immunolabeling density was evident between CFA‐treated and untreated mice. Most importantly, the CFA‐induced changes in &dgr;OR plasma membrane insertion seen in WT animals were not present in the spinal cord of &mgr;OR KO mice. These results demonstrate that the integrity of &mgr;OR is necessary for CFA‐induced changes in &dgr;OR trafficking to occur and suggest that these changes could be elicited by stimulation of &mgr;OR by endogenous opioids released in response to chronic inflammatory pain.

Remodelling of spinal nociceptive mechanisms in an animal model of monoarthritis

Intra‐articularly injected complete Freunds adjuvant creates in rats a chronic monoarthritis suitable for studying neuronal plasticity and chronic pain. Using such a model, we report electrophysiological and morphological evidence of alterations in somatosensory synaptic function. In arthritic rats, the baseline activity of dorsal spinal cord wide dynamic range or nociceptive‐specific neurons was greater than in control animals. Moreover, neuronal responses elicited by an innocuous stimulation with von Frey filaments applied to the arthritic joint were greater in amplitude and produced the afterdischarge that normally characterizes a nociceptive response. In contrast to the response in control animals, passive movement of the arthritic joint produced an increase in the amplitude of the response of these neurons to iontophoretic application of glutamate receptor agonists over a time frame of 10–30 min. This potentiation was blocked by pretreatment with a neurokinin‐1 (NK‐1) receptor antagonist, suggesting the involvement of substance P. Ultrastructural analysis of the dorsal horn revealed that movement of the arthritic joint also induced NK‐1 receptor internalization, indicative of nociception. Morphological examination revealed significantly increased expression of substance P and its receptor within the superficial dorsal horn of monoarthritic animals. These unique functional and chemical changes reflect alterations in both presynaptic and postsynaptic mechanisms in nociceptive transmission at the spinal level. Thus, although treatment of arthritis should obviously target its peripheral aetiology, targeting its central components is a logical therapeutic complementary objective.

Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction.

The mesolimbic dopamine system comprises neurons in the ventral tegmental area (VTA) and substantia nigra (SN), projecting to the ventral striatum. This system was originally described to mediate pleasure and goal-directed movement associated with rewarding stimuli.70 However, it is now clear that dopamine, although crucial for reward processing, drives not the hedonic experience of reward (“liking”) but rather the instrumental behavior of reward-driven actions (“wanting”).6 Phasic dopamine acts as an incentive salience signal underlying reinforcement learning.57,59 Moreover, aversive stimuli, such as pain, also stimulate dopamine, further diminishing the idea of dopamine as a “reward” signal.9,10 Recent studies suggest that dopamine neurons in the VTA and SN form a heterogeneous population tuned to either (or both) aversive or rewarding stimuli.3,8,30,39 This review will summarize our current understanding of the role of the mesolimbic dopamine system in acute pain and the changes that occur in chronic pain.