Conditional Analgesia from Spinally Transplanted Adrenal Chromaffin Cells

Pain. Jan, 2002  |  Pubmed ID: 11790482

Virally Mediated Delivery of Enkephalin and Other Neuropeptide Transgenes in Experimental Pain Models

Annals of the New York Academy of Sciences. Oct, 2002  |  Pubmed ID: 12438172

We have constructed recombinant herpes simplex virus type 1 vectors for delivery of genes to sensory neurons in an attempt to modulate nociception. Delivery of recombinant viruses to the skin of mice results in expression of encoded complementary DNA (cDNA) genes in DRG neurons within three to four days. Expression of marker genes persists for at least 10 weeks. Testing of baseline thermal nociceptive latencies at the site of virus application revealed no differences between a control virus and a virus encoding human preproenkephalin (hPPE) when performed at either low stimulus intensities (C-fiber activation) or high stimulus intensities (Adelta neurons). By contrast, sensitization of nociceptors by capsaicin or dimethylsulfoxide was reduced or abolished by infection with the virus encoding hPPE, but not by a control virus. These antihyperalgesic responses are mediated by opioids released at the central terminals of the primary afferents because they are blocked by intrathecal administration of the opioid antagonist naloxone. Similar experiments performed in macaques demonstrated an antihyperalgesic effect of the herpes virus vector encoding hPPE. This hPPE-encoding virus was also tested in a model of neuropathic pain in mice, with similar effect. A virus containing an antisense cDNA for calcitonin gene-related peptide precursor (ACGRP) has also been constructed and found to reverse C-fiber hyperalgesia caused by application of capsaicin to the skin for up to 14 weeks postinfection. These results raise the possibility that herpes-mediated, gene-based approaches to treat chronic pain states may be useful in therapy of chronic pain in humans.

Conformation-dependent Effects of VIP on Nociception in Rats

Peptides. Apr, 2003  |  Pubmed ID: 12860207

The purpose of this study was to determine whether intrathecal injection of aqueous (random coil) vasoactive intestinal peptide (VIP) and VIP self-associated with sterically stabilized phospholipid micelles (alpha-helix VIP) at the lower lumbar vertebral level modulates foot withdrawal latency to low and high rate noxious radiant skin heating in anesthetized rats. We found that intrathecal random coil VIP evoked a significant bimodal, concentration-dependent response, early potent antinociception followed by hyperalgesia, during exposure to low and high rates of skin heating (P<0.05). Intrathecal alpha-helix VIP elicited a qualitatively similar response to that of random coil VIP except that the rate of decay of antinociception was faster and slower at low and high rates of skin heating, respectively. In addition, a low concentration of alpha-helix VIP evoked a potent late antinociception not observed with random coil VIP. Taken together, these data indicate that VIP modulates somatosensory processing in the lumbosacral spinal cord of rats in a complex fashion, and that this response is dependent, in part, on the conformation of VIP in the vicinity of target cells in the peripheral nervous system.

Afferent Fiber-selective Shift in Opiate Potency Following Targeted Opioid Receptor Knockdown

Pain. Dec, 2003  |  Pubmed ID: 14659519

Spinal application of opiates is the cornerstone of potent analgesia. In the present study, opiate analgesia was investigated after cutaneous application of a recombinant herpes simplex virus type-1 (HSV-1) encoding micro-opioid receptor (microOR) cDNA in reverse orientation with respect to the human cytomegalovirus early enhancer-promoter. Hind paw application of this recombinant vector was used in order to attenuate expression of the microOR in primary afferents and determine whether recombinant vector application would differentially affect the antinociceptive effects of the specific microOR agonist, [D-Ala(2),N-MePhe(4),Gly-ol(5)] enkephalin (DAMGO), on behavioral responses mediated by C- and Adelta-thermonociceptors. The recombinant vector encoding the Escherichia coli lacZ gene marker, KHZ, served as a control virus. Dorsal hind paw surfaces of female Swiss-Webster mice were treated with one of these two viruses (1x10(8)pfu, 10 microl) or vehicle (uninfected). Immunohistochemistry and quantitative image analyses revealed decreased microOR expression in the superficial dorsal horns ipsilateral to hind paws treated with AMOR, but not KHZ. To add, behavioral foot withdrawal latencies of AMOR- and KHZ-treated hind paws demonstrated dose-dependent antinociception after intrathecal DAMGO administration. However, cutaneous application of dorsal hind paw surfaces treated with AMOR, but not KHZ, caused a rightward shift in the C-fiber dose-response, thus, indicating a loss of potency of intrathecal DAMGO. Loss or diminution of DAMGO potency during Adelta-fiber-mediated responses was not observed. These immunohistochemistry and behavioral results of novel, recombinant HSV-1 vector microOR 'knock-down' in nociceptor afferent fibers provide additional evidence for presynaptic localization of microORs on central C-, but not Adelta-terminals.

Reversal of Ongoing Thermal Hyperalgesia in Mice by a Recombinant Herpesvirus That Encodes Human Preproenkephalin

Molecular Therapy : the Journal of the American Society of Gene Therapy. Jan, 2004  |  Pubmed ID: 14741774

Herpesvirus-mediated transfer of the human preproenkephalin gene to primary afferent nociceptors prevents phasic thermal allodynia/hyperalgesia in mice. It is not known, however, whether similar viral treatments would reverse ongoing or chronic pain and allodynia/hyperalgesia. To this end, mice were given intrathecal injections of pertussis toxin (PTX), which produces a weeks-long thermal hyperalgesia apparently by uncoupling certain G proteins from inhibitory neurotransmitter receptors. This treatment produced profound thermal hyperalgesia in both Adelta and C-fiber thermonociceptive tests lasting at least 6 weeks. However, treatment of skin surfaces with an enkephalin-encoding herpesvirus, but not control virus or vehicle, completely reversed this hyperalgesia. This profound anti-hyperalgesia was observed for both Adelta- and C-fiber-mediated responses. Interestingly, however, while the anti-hyperalgesic effect of the enkephalin-encoding virus on C-fiber-mediated responses was reversed by intrathecal application of micro or delta opioid antagonists, only delta antagonists reversed the effect of this virus on Adelta hyperalgesia. Thus, virus-mediated delivery of the proenkephalin cDNA reverses thermal hyperalgesia produced by PTX-induced ribosylation of inhibitory G proteins by an opioid-mediated mechanism. These results suggest that herpesvirus vectors encoding analgesic peptides may be useful in attenuating centrally mediated, ongoing neuropathic pain and/or hyperalgesia.

Differential Opioid Inhibition of C- and A Delta- Fiber Mediated Thermonociception After Stimulation of the Nucleus Raphe Magnus

Anesthesia and Analgesia. Feb, 2004  |  Pubmed ID: 14742380

Although the importance of the nucleus raphe magnus in descending inhibitory control of nociception is clear, it is not known whether these effects are equivalent for different types of nociception. Thus, we examined the differential inhibition of behavioral responses evoked by A delta or C fiber thermonociceptor activation by electrical stimulation of nucleus raphe magnus neurons as well as the involvement of different classes of opiate receptors in this inhibition. In general, it was necessary to apply twice as much current to the nucleus raphe magnus to produce criterion antinociception for A delta mediated versus C fiber mediated nociceptive responses. Intrathecal administration of the nonselective opioid receptor antagonist, naltrexone, or the delta(1) opioid receptor antagonist, naltrindole, attenuated both A delta and C fiber antinociception induced by nucleus raphe magnus stimulation with similar efficacy. In contrast, intrathecal administration of naloxonazine, a micro specific opioid receptor antagonist, or naltriben, a delta(2) specific opioid receptor antagonist, preferentially attenuated nucleus raphe magnus induced antinociception for C fiber responses when compared with A delta mediated responses. These findings suggest that nociception evoked by the activation of A delta or C fiber nociceptors is under pharmacologically distinguishable descending control from the nucleus raphe magnus. IMPLICATIONS: Opiates differentially inhibit pain produced by the activation of myelinated or unmyelinated pain sensing neurons, a distinction that is clinically important. This article demonstrates that the brain's own pain control system operates with similar selectivity, and that this selectivity is partly mediated by different opiate receptor subtypes.

Protein Kinase C Epsilon and Gamma: Involvement in Formalin-induced Nociception in Neonatal Rats

The Journal of Pharmacology and Experimental Therapeutics. May, 2004  |  Pubmed ID: 14762097

The central nervous system undergoes dynamic changes as it matures. However, until recently, very little was known about the impact of these changes on pain and analgesia. This study tested the hypothesis that the epsilon and gamma isozymes of protein kinase C (PKC) contribute to formalin-induced nociception in an age-dependent manner. Expression of epsilon and gamma PKC and the contributions of these isozymes in formalin-induced nociception was examined in postnatal day 7, 15, and 21 rats. epsilonPKC expression in dorsal root ganglion neurons and gammaPKC expression in lamina II of the spinal cord increased from the first to the third postnatal week. Coupling immunohistochemical and Western analysis, translocation of epsilonPKC followed intraplantar formalin in all ages. In contrast, formalin-induced gammaPKC translocation was observed only in postnatal day 21 rats. Behaviorally, intrathecal administration of the epsilonPKC-specific inhibitor (epsilonV1-2) attenuated phase 1 and phase 2 formalin behaviors at all ages. In contrast, intrathecal administration of the gammaPKC-specific inhibitor (gammaV5-3) attenuated only phase 2 responses in postnatal day 15 and 21 rats. Functionally, inhibition of epsilonPKC decreased capsaicin-stimulated release of glutamate and calcitonin gene-related peptide in spinal cords isolated from postnatal day 7 rats. These results suggest that epsilonPKC age independently mediates inflammatory pain produced by intraplantar formalin. In contrast, gammaPKC contributes to formalin-induced nociception in an age-dependent manner. Identifying the molecular mechanisms responsible for age-specific patterns of nociception is necessary for the rational development of novel therapeutic strategies for treating pediatric pain.

Antinociceptive Action of a P38alpha MAPK Inhibitor, SD-282, in a Diabetic Neuropathy Model

Pain. Jun, 2004  |  Pubmed ID: 15157702

Diabetes can induce a bewildering list of sensory changes, including alteration in pain sensitivity. Painful diabetic neuropathy is refractory to most common analgesics. This study examined the effect of a p38alpha MAPK inhibitor, SD-282, on mechanical allodynia, thermal hyperalgesia, and formalin-evoked nociception in streptozotocin-induced diabetic rats. Four-week diabetic rats exhibited mechanical allodynia, decreased mechanical thresholds, and C- and Adelta-fiber mediated thermal hyperalgesia. Mechanical and thermal responses were measured in diabetic rats following acute and repeated intraperitoneal administration of vehicle, 15 or 45 mg/kg SD-282. Mechanical allodynia was reversed by acute and repeated administration of 15 and 45 mg/kg SD-282. Repeated administration of 15 or 45 mg/kg SD-282 prevented the exacerbation of C-, but not Adelta-fiber, mediated thermal hyperalgesia. Repeated administration of 45 mg/kg SD-282 attenuated flinching behaviors during the quiescent period and the second phase of the formalin response in diabetic rats. Acute and repeated administration of 15 or 45 mg/kg SD-282 had no effect on mechanical, thermal or formalin responses in age-matched control rats. These results indicate a potential therapeutic value of p38alpha MAPK inhibitors in the treatment of aberrant pain sensitivity produced by diabetes.

Porcine Chromaffin Cells, Culture, and Transplant for Antinociceptive Effects in Rodents and Primates

Neurological Research. Oct, 2004  |  Pubmed ID: 15494107

It has been shown that xenografts and allografts of spinally transplanted adrenal chromaffin cells produce antinociception in animals and pain relief in patients with cancer pain. As there is a very limited availability of human adrenal tissue to serve as allografts, the clinical need for xenogeneic chromaffin cells as transplants is obvious. Bovine adrenal glands as a steady source of chromaffin cells have been extensively studied. There is however concern about the possible infection in humans with retrovirus following transplantation. The purpose of this study is to use the pig as a preferred donor animal species for xenotransplantation into rat and monkey. As pigs have been cloned, this opens the door to gene-targeted technologies and allows for genetic modifications, which possibly could improve the efficacy and safety of chromaffin cell transplantation. Porcine chromaffin cells were isolated from adrenal glands of 6-8-month-old pigs. After culturing cells for 1 week in a medium containing serum, the release of met-enkephalin and norepinephrine from the cells was detected by high-performance liquid chromatography and radioimmunoassay with nicotine stimulation, lasting approximately 3 weeks. Transplantation of these cells into the subarachnoid space of rats produced antinociceptive effects on Adelta and C fiber-mediated responses lasting 2-3 weeks. Similar findings were observed in studies with macaque monkeys. Compared with the same number of bovine chromaffin cells, porcine chromaffin cells showed a more robust and longer antinociceptive effect, and could be a better source of cells for human transplantation.

Differential Activation of Trigeminal C or Adelta Nociceptors by Infrared Diode Laser in Rats: Behavioral Evidence

Brain Research. Mar, 2005  |  Pubmed ID: 15777763

Radiant heat is often used for studying thermal nociception, although inherent characteristics such as the broad spectrum of applied wavelengths of typical light sources limit control over and repeatability of stimuli. To overcome these problems, we used a diode infrared laser-based stimulator (wavelength: 980 nm) for selectively stimulating trigeminal Adelta or C thermonociceptors in rats. To provide indirect evidence for nociceptor-selective stimulation, we tested the effects of capsaicin, dimethylsulfoxide (DMSO), and morphine on withdrawal latencies for long pulses with a low current (hypothesized to selectively stimulate C nociceptors) and for threshold currents of short pulses with high current (hypothesized to selectively stimulate Adelta nociceptors) in lightly anesthetized rats. Nonmem analysis was used to perform pharmacodynamic modeling. The measured baseline withdrawal latency for long pulses was 12.5 +/- 0.3 s which was changed significantly to 6.7 +/- 0.4 s after applying topical capsaicin which selectively sensitizes C nociceptors and to 16.5 +/- 1.3 s after 1.0 mg/kg morphine which preferentially attenuates C fiber nociception. Topical DMSO which appears to selectively sensitize Adelta afferents did not significantly alter withdrawal latencies to the long pulses. Fitted threshold currents for short pulses after DMSO were however significantly lower (974 +/- 53 mA vs. 1113 +/- 12 mA for baseline) indicating Adelta sensitization. Capsaicin and morphine did not significantly change threshold currents. Best Nonmem fits for the long pulse were obtained using a model assuming no DMSO effect, but a different inter-individual variability after applying this substance. For the short pulse, a model assuming no capsaicin or morphine effect, but again allowing different inter-individual variabilities after applying these drugs, best described the data. We conclude that different settings of the stimulator used in this study were capable of selectively activating trigeminal Adelta or C thermonociceptors.

GABAB Receptors on Central Terminals of C-afferents Mediate Intersegmental Adelta-afferent Evoked Hypoalgesia

European Journal of Pain (London, England). Jun, 2005  |  Pubmed ID: 15862472

The current study tested the hypothesis that repetitive activation of sciatic Adelta-afferents evokes a saphenous C-afferent hypoalgesia mediated by pre-synaptic GABA(B) receptors. Tonic activation of sciatic Adelta-afferents was produced by cutaneous application of dimethyl sulfoxide (DMSO) followed by repetitive thermal activation of Adelta-afferents on the dorsolateral hind paw. The tonic activation of sciatic Adelta-afferents produced hypoalgesia in saphenous C-afferents. Intrathecal administration of the GABA(B) receptor antagonist, saclofen, attenuated saphenous hypoalgesia demonstrating at least partial mediation by central GABA(B) receptors. To determine if this central GABA(B) receptor activation occurs at pre-synaptic primary afferent terminals or postsynaptic spinal cord neurons, the dorsal hind paws of mice were infected with a recombinant herpes simplex virus type 1 (HSV-1) designed to selectively knock down expression of the GABA(B1a) receptor subunit (PAGB1a) in primary afferents or a control virus encoding the E. coli lacZ gene (PZ). Four weeks after infection, GABA(B) receptor immunoreactivity in the superficial dorsal horns ipsilateral to PAGB1a application was reduced and hypoalgesia in saphenous C-afferents was attenuated when compared to PZ-infected mice. These findings indicate an intersegmental, sciatic Adelta-afferent-evoked hypoalgesic effect on saphenous C-afferent responses that is mediated by pre-synaptic GABA(B) receptors on the terminals of those C-afferents.

Attenuation of Pain Perception After Transposition of the Greater Omentum to the Cauda Equina Region of Rats--a Preliminary Observation

Neurological Research. Sep, 2005  |  Pubmed ID: 16157009

This paper addresses a specific experimental design to suggest the possible role of the greater omentum in the modulation of pain in rats.

Do Guidelines for Severe Mental Illness Promote Physical Health and Well-being?

Journal of Psychopharmacology (Oxford, England). Nov, 2005  |  Pubmed ID: 16280343

The effective management of individuals with severe mental illnesses (SMIs) requires an holistic approach that offers reliable symptom control, but also addresses other clinical, emotional and social needs. The physical health of individuals with an SMI is often poor, with many being overweight or obese, having hypertension, diabetes or dyslipidaemia, and at significant risk of developing cardiovascular disease or other comorbidities. We have recently reviewed current UK and US guidelines for the management of individuals with schizophrenia and bipolar disorder, and found very different approaches to the holistic care of people with SMIs, especially in relation to the management of physical health and cardiovascular risk. UK guidelines acknowledge the high risk of physical morbidity and mortality in individuals with an SMI, but fail to address in detail the specifics of physical health monitoring and lifestyle management. US guidelines are more descriptive in terms of the type and extent of monitoring recommended, but there are inconsistencies between the guidelines produced by different organizations, and studies in the field suggest that none of them is being adequately implemented. Clear and consistent recommendations on how and when to monitor weight, cardiovascular function, and metabolic parameters and, importantly, what to do with the results, would support clinicians wishing to integrate physical and mental healthcare. Publication of specific recommendations on evidence-based physical health interventions that can work for people with SMIs would also help primary care and mental health services improve general well-being in their patients with severe mental illnesses.

Recombinant Herpes Vector-mediated Analgesia in a Primate Model of Hyperalgesia

Molecular Therapy : the Journal of the American Society of Gene Therapy. Mar, 2006  |  Pubmed ID: 16288901

Some chronic pain syndromes are characterized by episodes of intense burning and hyperalgesia in localized areas of skin. These sensations are thought to be mediated, at least in part, by the activity of damaged, unmyelinated C nociceptors. These phenomena were modeled by assaying responses of macaques to thermal and chemical stimuli that produced periodic activation and sensitization of C nociceptors. Upon validation of this method, a recombinant herpes simplex vector encoding human preproenkephalin was topically applied to the dorsal surface of the feet of the monkeys. Immunohistochemistry and radioimmunoassay revealed that enkephalin peptides were being produced in releasable pools in sensory neurons innervating the treated skin area. Behavioral responses evoked by periodic sensitization and activation of C nociceptors innervating the vector-treated skin area revealed a substantial and long-lasting (at least 20 weeks) antihyperalgesic and analgesic effect limited to the areas to which the virus was applied. This approach may be a viable means of treating localized cutaneous burning pain and hyperalgesia.

Blockade of the Complement C5a Receptor Reduces Incisional Allodynia, Edema, and Cytokine Expression

Anesthesiology. Jun, 2006  |  Pubmed ID: 16732100

Activation of the complement system is one component of the inflammatory response. Various components of the complement system participate in killing foreign organisms, recruiting immune cells, enhancing edema, and stimulating cytokine formation. Complement-mediated enhancement of the inflammation surrounding surgical incisions may increase pain.

ASIC3 in Muscle Mediates Mechanical, but Not Heat, Hyperalgesia Associated with Muscle Inflammation

Pain. May, 2007  |  Pubmed ID: 17134831

Peripheral initiators of muscle pain are virtually unknown, but likely key to development of chronic pain after muscle insult. The current study tested the hypothesis that ASIC3 in muscle is necessary for development of cutaneous mechanical, but not heat, hyperalgesia induced by muscle inflammation. Using mechanical and heat stimuli, we assessed behavioral responses in ASIC3-/- and ASIC3+/+ mice after induction of carrageenan muscle inflammation. ASIC3-/- mice did not develop cutaneous mechanical hyperalgesia after muscle inflammation when compared to ASIC3+/+ mice; heat hyperalgesia developed similarly between groups. We then tested if the phenotype could be rescued in ASIC3-/- mice by using a recombinant herpes virus vector to express ASIC3 in skin (where testing occurred) or muscle (where inflammation occurred). Infection of mouse DRG neurons with ASIC3-encoding virus resulted in functional expression of ASICs. Injection of ASIC3-encoding virus into muscle or skin of ASIC3-/- mice resulted in ASIC3 mRNA in DRG and protein expression in DRG and the peripheral injection site. Injection of ASIC3-encoding virus into muscle, but not skin, resulted in development of mechanical hyperalgesia similar to that observed in ASIC3+/+ mice. Thus, ASIC3 in primary afferent fibers innervating muscle is critical to development of hyperalgesia that results from muscle insult.

Antihyperalgesic Effect of a Recombinant Herpes Virus Encoding Antisense for Calcitonin Gene-related Peptide

Anesthesiology. Jun, 2007  |  Pubmed ID: 17525595

Calcitonin gene-related peptide (CGRP) is contained in and released by small-diameter, nociceptive primary afferent sensory neurons. Upon spinal release, one of the effects of CGRP seems to be to sensitize dorsal horn neurons to subsequent input from nociceptive afferents and, consequently, to induce a behavioral hyperalgesia. Therefore, attenuating evoked release of CGRP from central terminals of nociceptors should have an antihyperalgesic effect.

Treatment of Inflamed Pancreas with Enkephalin Encoding HSV-1 Recombinant Vector Reduces Inflammatory Damage and Behavioral Sequelae

Molecular Therapy : the Journal of the American Society of Gene Therapy. Oct, 2007  |  Pubmed ID: 17565349

This study assessed the efficacy of pancreatic surface delivered enkephalin (ENK)-encoding herpes simplex virus type 1 (HSV-1) on spontaneous behaviors and spinal cord and pancreatic enkephalin expression in an experimental pancreatitis model. Replication-defective HSV-1 with proenkephalin complementary DNA (cDNA) (HSV-ENK) or control beta-galactosidase cDNA (HSV-beta-gal), or media vehicle (Veh) was applied to the pancreatic surface of rats with dibutyltin dichloride (DBTC)-induced pancreatitis. Spontaneous exploratory behavioral activity was monitored on days 0 and 6 post DBTC and vector treatments. The pancreas, thoracic dorsal root ganglia (DRG, T9-10), and spinal cord (T9-10) were immunostained for met-enkephalin (met-ENK), beta-gal, and HSV-1 proteins. Spinal cord was also immunostained for c-Fos, and pancreas was stained for the inflammatory marker regulated on activation, normal T-cells expressed and secreted (RANTES), mu-opioid receptor, and hemotoxylin/eosin. On day 6, compared to pancreatitis and vector controls, the DBTC/HSV-ENK treated rats had significantly improved spontaneous exploratory activities, increased met-ENK staining in the pancreas and spinal cord, and normalized c-Fos staining in the dorsal horn. Histopathology of pancreas in DBTC/HSV-ENK treated rats showed preservation of acinar cells and cytoarchitecture with minimal inflammatory cell infiltrates, compared to severe inflammation and acinar cell loss seen in DBTC/HSV-beta-gal and DBTC/Veh treated rats. Targeted transgene delivery and met-ENK expression successfully produced decreased inflammation in experimental pancreatitis.

A Well-being Programme in Severe Mental Illness. Reducing Risk for Physical Ill-health: a Post-programme Service Evaluation at 2 Years

European Psychiatry : the Journal of the Association of European Psychiatrists. Oct, 2007  |  Pubmed ID: 17765483

Cardiovascular disease is more prevalent in patients with severe mental illness (SMI) than in the general population.

Morphine Reduces Local Cytokine Expression and Neutrophil Infiltration After Incision

Molecular Pain. 2007  |  Pubmed ID: 17908329

Inflammation and nociceptive sensitization are hallmarks of tissue surrounding surgical incisions. Recent studies demonstrate that several cytokines may participate in the enhancement of nociception near these wounds. Since opioids like morphine interact with neutrophils and other immunocytes, it is possible that morphine exerts some of its antinociceptive action after surgical incision by altering the vigor of the inflammatory response. On the other hand, keratinocytes also express opioid receptors and have the capacity to produce cytokines after injury. Our studies were directed towards determining if opioids alter cytokine production near incisions and to identify cell populations responsible for producing these cytokines.

Effect of Anti-NGF Antibodies in a Rat Tibia Fracture Model of Complex Regional Pain Syndrome Type I

Pain. Aug, 2008  |  Pubmed ID: 18083307

Tibia fracture in rats evokes chronic hindpaw warmth, edema, allodynia, and regional osteopenia resembling the clinical characteristics of patients with complex regional pain syndrome type I (CRPS I). Nerve growth factor (NGF) has been shown to support nociceptive and other types of changes found in neuropathic pain models. We hypothesized that anti-NGF antibodies might reduce one or more of the CRPS I-like features of the rat fracture model. For our studies one distal tibia of each experimental rat was fractured and casted for 4 weeks. The rats were injected with anti-NGF or vehicle at days 17 and 24 post-fracture. Nociceptive testing as well as assessment of edema and hindpaw warmth were followed during this period. Molecular and biochemical techniques were used to follow cytokine, NGF and neuropeptide levels in hindpaw skin and sciatic nerves. Lumbar spinal cord Fos immunostaining was performed. Bone microarchitecture was measured using microcomputed tomography (microCT). We found that tibia fracture upregulated NGF expression in hindpaw skin and tibia bone along with sciatic nerve neuropeptide content. We also found nociceptive sensitization, enhanced spinal cord Fos expression, osteopenia and enhanced cytokine content of hindpaw skin on the side of the fracture. Anti-NGF treatment reduced neuropeptide levels in sciatic nerve and reduced nociceptive sensitization. There was less spinal cord Fos expression and bone loss in the anti-NGF treated animals. Conversely, anti-NGF did not decrease hindpaw edema, warmth or cytokine production. Collectively, anti-NGF reduced some but not all signs characteristic of CRPS illustrating the complexity of CRPS pathogenesis and NGF signaling.

Chronic Morphine Administration Enhances Nociceptive Sensitivity and Local Cytokine Production After Incision

Molecular Pain. 2008  |  Pubmed ID: 18294378

The chronic use of opioids prior to surgery leads to lowered pain thresholds and exaggerated pain levels after these procedures. Several mechanisms have been proposed to explain this heightened sensitivity commonly termed opioid-induced hyperalgesia (OIH). Most of these proposed mechanisms involve plastic events in the central or peripheral nervous systems. Alterations in the abundance of peripheral mediators of nociception have not previously been explored.

Enkephalin-encoding Herpes Simplex Virus-1 Decreases Inflammation and Hotplate Sensitivity in a Chronic Pancreatitis Model

Molecular Pain. 2008  |  Pubmed ID: 18307791

A chronic pancreatitis model was developed in young male Lewis rats fed a high-fat and alcohol liquid diet beginning at three weeks. The model was used to assess time course and efficacy of a replication defective herpes simplex virus type 1 vector construct delivering human cDNA encoding preproenkephalin (HSV-ENK).

Joint Capsule Treatment with Enkephalin-encoding HSV-1 Recombinant Vector Reduces Inflammatory Damage and Behavioural Sequelae in Rat CFA Monoarthritis

The European Journal of Neuroscience. Mar, 2008  |  Pubmed ID: 18364035

This study assessed enkephalin expression induced by intra-articular application of recombinant, enkephalin-encoding herpes virus (HSV-1) and the impact of expression on nociceptive behaviours and synovial lining inflammation in arthritic rats. Replication-conditional HSV-1 recombinant vectors with cDNA encoding preproenkephalin (HSV-ENK), or control transgene beta-galactosidase cDNA (HSV-beta-gal; control) were injected into knee joints with complete Freund's adjuvant (CFA). Joint temperatures, circumferences and nociceptive behaviours were monitored on days 0, 7, 14 and 21 post CFA and vector treatments. Lumbar (L4-6) dorsal root ganglia (DRG) and spinal cords were immunostained for met-enkephalin (met-ENK), beta-gal, HSV-1 proteins and Fos. Joint tissues were immunostained for met-ENK, HSV-1 proteins, and inflammatory mediators Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES) and cyclo-oxygenase-2, or stained with haematoxylin and eosin for histopathology. Compared to exuberant synovial hypertrophy and inflammatory cell infiltration seen in arthritic rats treated with CFA only or CFA and HSV-beta-gal, the CFA- and HSV-ENK-treated arthritic rats had: (i) striking preservation of synovial membrane cytoarchitecture with minimal inflammatory cell infiltrates; (ii) significantly improved nociceptive behavioural responses to mechanical and thermal stimuli; (iii) normalized Fos staining in lumbar dorsal horn; and (iv) significantly increased met-ENK staining in ipsilateral synovial tissue, lumbar DRG and spinal cord. The HSV-1 and transgene product expression were confined to ipsilateral lumbar DRG (HSV-1, met-ENK, beta-gal). Only transgene product (met-ENK and beta-gal) was seen in lumbar spinal cord sections. Targeted delivery of enkephalin-encoding HSV-1 vector generated safe, sustained opioid-induced analgesia with protective anti-inflammatory blunting in rat inflammatory arthritis.

Categorical Prevalence and Severity of Hyperprolactinaemia in Two UK Cohorts of Patients with Severe Mental Illness During Treatment with Antipsychotics

Journal of Psychopharmacology (Oxford, England). Mar, 2008  |  Pubmed ID: 18477621

Hyperprolactinaemia may be associated with hidden longer-term consequences, such as osteoporosis, bone fractures, pituitary tumours and breast cancer. Prolactin data from clinical trials is not always reported in a categorical manner and does not always allow the risk of hyperprolactinaemia to be evaluated for specific patient cohorts. Patients participating in a physical health management programme in the UK for severe mental illness patients--the Well-being Support Programme--had prolactin measurements made regardless of symptoms. Prolactin data from the complete cohort of 178 patients receiving antipsychotics in Leeds and London are reported. Hyperprolactinaemia was measured in 33.1% but more commonly in females than males (47.3% and 17.6%) and was associated with all antipsychotics except clozapine. The highest prevalence rates were found in amisulpride (n=20) 89%, risperidone long-acting intramuscular injection (LAIM) 67% (n=6) and risperidone (n=30) 55% used as antipsychotic monotherapy. Clinically Significant hyperprolactinaemia (>1000 mIU/L approximately 47 ng/ml) was measured in 15.8% of patients, predominantly in females. Levels >2000 mIU/L approximately 95 ng/ml in 6.2% of the complete cohort. Clinicians may wish to add prolactin measurement to the routine laboratory parameters currently measured for some antipsychotics and should be advised of the potential longer-term consequences of hidden hyperprolactinaemia.

Antipsychotics and Hyperprolactinaemia: Clinical Recommendations

Journal of Psychopharmacology (Oxford, England). Mar, 2008  |  Pubmed ID: 18477626

A group of international experts in psychiatry, medicine, toxicology and pharmacy assembled to undertake a critical examination of the currently available clinical guidance on hyperprolactinaemia. This paper summarises the group's collective views and provides a summary of the recommendations agreed by the consensus group to assist clinicians in the recognition, clinical assessment, investigation and management of elevated plasma prolactin levels in patients being treated for severe mental illness. It also deals with the special problems of particular populations, gives advice about information that should be provided to patients, and suggests a strategy for routine monitoring of prolactin. The recommendations are based upon the evidence contained in the supplement 'Hyperprolactinaemia in schizophrenia and bipolar disorder: Clinical Implications' (2008). The guidance contained in this article is not intended to replace national guidance (such as that of the National Institute of Clinical Excellence), however, it does provide additional detail that is unlikely to be covered in existing guidelines, and focuses on areas of uncertainty and disagreement. We hope it will add to the debate about this topic.

Wake-up Call for British Psychiatry: Responses

The British Journal of Psychiatry : the Journal of Mental Science. Dec, 2008  |  Pubmed ID: 19043163

Role of Substance P Signaling in Enhanced Nociceptive Sensitization and Local Cytokine Production After Incision

Pain. Oct, 2009  |  Pubmed ID: 19660865

Substance P (SP) signaling facilitates nociceptive sensitization in various inflammatory and chronic pain models and we postulated that SP signaling might also contribute to the development of post-incisional hyperalgesia. These studies used mice with a deletion of the pre-protachykinin A gene (ppt-A(-/-)) which codes for SP to determine the role of SP signaling in post-incisional pain and in the increased cytokine and nerve growth factor (NGF) expression observed in the incised skin. SP deficient ppt-A(-/-) mice displayed reduced mechanical allodynia and heat hyperalgesia compared to the wild-type (wt) mice at all post-incision time points, despite similar baseline values (p<0.001). Furthermore, the NK-1 receptor antagonist LY303870 attenuated mechanical allodynia produced by incision in the wt mice (p<0.001). Incision also up-regulated IL-6, TNF-alpha and KC levels but not IL-1beta after 2h in the wt mice skin. However, ppt-A(-/-) mice had more skin NGF levels 2h post-incision. Subcutaneous hind paw SP injection produced acute and transient elevations of IL-1beta, IL-6, and KC but modest elevations in TNF-alpha levels in the wt mice. Systemic LY303870 reversed the SP-induced elevations of these cytokines. Hind paw injection of IL-6 and NGF dose dependently produced less mechanical allodynia in the ppt-A(-/-) compared to wt mice. Additionally, SP produced mechanical allodynia in a dose-dependent fashion in wt mice. Therefore, SP supports nociceptive sensitization after hind paw incision and potentially participates directly in modulating the intensity of inflammatory response in peri-incisional tissue.

Diagnostic Utility of Cytokine Biomarkers in the Evaluation of Acute Knee Pain

The Journal of Bone and Joint Surgery. American Volume. Oct, 2009  |  Pubmed ID: 19797564

The diagnosis of clinically important meniscal tears of the knee remains challenging, and it is unknown why only some injuries become painful. The role of inflammatory cytokines in generating pain following meniscal injury remains unclear. This study aimed to investigate the cytokine profile in patients with acute knee pain believed to be secondary to meniscal damage.

Epidural Interferon Gamma-immunoreactivity: a Biomarker for Lumbar Nerve Root Irritation

Spine. Oct, 2009  |  Pubmed ID: 19934811

Prospective observational cohort.

Managing Schizophrenia in Primary Care: the Utility of Remission Criteria As Outcome Indicators

Mental Health in Family Medicine. Jun, 2009  |  Pubmed ID: 22477899

The shared management of patients with schizophrenia in primary care can only succeed if underpinned by valid, easily administered and clinically relevant outcome measures. While conditions such as depression and anxiety lend themselves to this approach through the development, over a number of years, of patient- and observer-rated scales, schizophrenia still lacks the capacity for meaningful outcome measures. Recently, two international working groups have developed the concept of remission in schizophrenia and recommended a simple, brief and clinically valid measure based upon improvement in key symptoms over a specified time period. The authors consider this concept and its application to primary care both as a commissioning tool and to facilitate shared care of this chronic medical condition.

Cytokine Evaluation in Individuals with Low Back Pain Using Discographic Lavage

The Spine Journal : Official Journal of the North American Spine Society. Mar, 2010  |  Pubmed ID: 20207331

The pathophysiology underlying degenerative disc disease and its implication in painful syndromes remain unclear. However, spine magnetic resonance imaging (MRI) can demonstrate changes in disc water content and the annulus; provocative discography purportedly identifies degenerate discs causing serious low back pain; and biochemical assays have identified local inflammatory markers. No study to date has correlated pain on disc injection during discography evaluation with relevant MRI findings and biochemical markers.

Identification of a Complex Between Fibronectin and Aggrecan G3 Domain in Synovial Fluid of Patients with Painful Meniscal Pathology

Clinical Biochemistry. Jul, 2010  |  Pubmed ID: 20460120

We previously described a panel of four cytokines biomarkers in knee synovial fluid for acute knee pain associated with meniscal pathology. The cytokine biomarkers included interferon gamma (IFN-gamma), interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1beta). Validation studies using other immunologic techniques confirmed the presence of IL-6, MCP-1 and MIP-1beta, but not IFN-gamma. Therefore we sought the identity of the IFN-gamma signal in synovial fluid.

Trigeminal Antihyperalgesic Effect of Intranasal Carbon Dioxide

Life Sciences. Jul, 2010  |  Pubmed ID: 20561904

Clinical studies demonstrate attenuation of trigeminal-related pain states such as migraine by intranasal CO(2) application. This study investigated the underlying mechanisms of this observation and its potential use to reverse trigeminal pain and hypersensitivity.

Thermal Nociceptive Properties of Trigeminal Afferent Neurons in Rats

Molecular Pain. 2010  |  Pubmed ID: 20609212

Although nociceptive afferents innervating the body have been heavily studied form many years, much less attention has been paid to trigeminal afferent biology. In particular, very little is known concerning trigeminal nociceptor responses to heat, and almost nothing in the rat. This study uses a highly controlled and reproducible diode laser stimulator to investigate the activation of trigeminal afferents to noxious skin heating.

Caspase-1 Modulates Incisional Sensitization and Inflammation

Anesthesiology. Oct, 2010  |  Pubmed ID: 20823759

Surgical injury induces production and release of inflammatory mediators in the vicinity of the wound. They in turn trigger nociceptive signaling to produce hyperalgesia and pain. Interleukin-1β plays a crucial role in this process. The mechanism regulating production of this cytokine after incision is, however, unknown. Caspase-1 is a key enzyme that cleaves prointerleukin-1β to its active form. We hypothesized that caspase-1 is a crucial regulator of incisional interleukin-1β levels, nociceptive sensitization, and inflammation.

Continuous Subcutaneous Instillation of Bupivacaine Compared to Saline Reduces Interleukin 10 and Increases Substance P in Surgical Wounds After Cesarean Delivery

Anesthesia and Analgesia. Dec, 2010  |  Pubmed ID: 20861424

Recent evidence suggests that locally delivered local anesthetics may exert tissue-damaging effects such as chondrolysis after intraarticular injection. Alteration of the inflammatory response is a potential mechanism for local anesthetic-induced tissue toxicity. In this study, we tested the effects of continuous local anesthetic infiltration on the release of inflammatory and nociceptive mediators in skin wounds after cesarean delivery.

Cytokine Profiling in Acute Anterior Cruciate Ligament Injury

Arthroscopy : the Journal of Arthroscopic & Related Surgery : Official Publication of the Arthroscopy Association of North America and the International Arthroscopy Association. Oct, 2010  |  Pubmed ID: 20887928

To evaluate the presence and relative concentrations of cytokines, known to be involved in the inflammatory cascade, in acute anterior cruciate ligament (ACL) injury.

The Role of Interleukin-1 in Wound Biology. Part I: Murine in Silico and in Vitro Experimental Analysis

Anesthesia and Analgesia. Dec, 2010  |  Pubmed ID: 20889942

Wound healing is a multistep, complex process that involves the coordinated action of multiple cell types. Conflicting results have been obtained when conventional methods have been used to study wound biology. Therefore, we analyzed the wound response in a mouse genetic model.

The Role of Interleukin-1 in Wound Biology. Part II: In Vivo and Human Translational Studies

Anesthesia and Analgesia. Dec, 2010  |  Pubmed ID: 20889944

In the accompanying paper, we demonstrate that genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production through altering the amount of interleukin (IL)-1 produced. We further investigate the role of IL-1 in incisional wound biology and its effect on wound chemokine production in vivo and whether this mechanism could be active in human subjects.

Selective Nociceptor Activation in Volunteers by Infrared Diode Laser

Molecular Pain. 2011  |  Pubmed ID: 21426575

Two main classes of peripheral sensory neurons contribute to thermal pain sensitivity: the unmyelinated C fibers and thinly myelinated Aδ fibers. These two fiber types may differentially underlie different clinical pain states and distinctions in the efficacy of analgesic treatments. Methods of differentially testing C and Aδ thermal pain are widely used in animal experimentation, but these methods are not optimal for human volunteer and patient use. Thus, this project aimed to provide psychophysical and electrophysiological evidence that whether different protocols of infrared diode laser stimulation, which allows for direct activation of nociceptive terminals deep in the skin, could differentially activate Aδ or C fiber thermonociceptors in volunteers.

Analgesic Effects of Tramadol, Tramadol-gabapentin, and Buprenorphine in an Incisional Model of Pain in Rats (Rattus Norvegicus)

Journal of the American Association for Laboratory Animal Science : JAALAS. Mar, 2011  |  Pubmed ID: 21439212

Postoperative pain management in laboratory animals relies heavily on a limited number of drug classes, such as opioids and nonsteroidal antiinflammatory drugs. Here we evaluated the effects of saline, tramadol, tramadol with gabapentin, and buprenorphine (n = 6 per group) in a rat model of incisional pain by examining thermal hyperalgesia and weight-bearing daily for 6 d after surgery. All drugs were administered preemptively and continued for 2 consecutive days after surgery. Rats treated with saline or with tramadol only showed thermal hyperalgesia on days 1 through 4 and 1 through 3 after surgery, respectively. In contrast, buprenorphine-treated rats showed no thermal hyperalgesia on days 1 and 2 after surgery, and rats given tramadol with gabapentin showed reduced thermal hyperalgesia on days 2 and 4. For tests of weight-bearing, rats treated with saline or with tramadol only showed significantly less ipsilateral weight-bearing on day 1 after surgery, whereas rats given either buprenorphine or tramadol with gabapentin showed no significant change in ipsilateral weight-bearing after surgery. These data suggest that tramadol alone provides insufficient analgesia in this model of incisional pain; buprenorphine and, to a lesser extent, tramadol with gabapentin provide relief of thermal hyperalgesia and normalize weight-bearing.

The Orofacial Formalin Test in Mice Revisited--effects of Formalin Concentration, Age, Morphine and Analysis Method

The Journal of Pain : Official Journal of the American Pain Society. Jun, 2011  |  Pubmed ID: 21481645

The orofacial formalin test is established in rats and was recently transferred to mice. The aim of this study was to determine the ideal formalin concentration for testing analgesic drugs, to examine alternatives for the assessment of nociceptive and non-nociceptive behavior as well as the effects of morphine and age on formalin-induced nociception. Formalin (.5, 1, 2.5, 5, 7.5, 10, and 15%) was injected into the vibrissa of mice. The cumulative nociceptive behavior was measured as well as nociceptive and non-nociceptive behavior based on a score that was recorded over a 5-second observation period once per minute. We also examined the effects of morphine on the nociceptive response induced by 2.5% formalin. Age-dependent differences were tested in the third part of the experiment. NONMEM was used to model the pharmacodynamic effects of formalin and morphine. Injection of formalin lead to a concentration-dependent increase in cumulative nociceptive behavior ratings as well as the specific nociceptive behavior 3 of scratching injection site with hindpaw (score 3). The formalin concentrations that lead to 50% of the maximum effect were 2.6 and 3.3%, respectively, for the continuous rating method and the scoring method. Morphine dose dependently suppressed the nociceptive behavior and the number of score 3 ratings of the nociceptive behavior. Age differences in behavior could not be detected by either analytic method. PERSPECTIVE: To improve the existing behavioral nociceptive assay for pain processed by the trigeminal system, we determined an ideal formalin concentration for the orofacial formalin test in mice, evaluated alternative timesaving analysis approaches, and investigated effects of morphine and age on formalin-induced nociception.

Care Clusters and Mental Health Payment by Results

The British Journal of Psychiatry : the Journal of Mental Science. Feb, 2012  |  Pubmed ID: 22297592

A Rodent Model of Trigeminal Neuralgia

Methods in Molecular Biology (Clifton, N.J.). 2012  |  Pubmed ID: 22351086

Trigeminal Neuralgia (Tic Douloureux) is a neuropathic pain syndrome caused by compression of the trigeminal nerve root and is characterized by severe paroxysms of pain in the face commonly triggered by light mechanical stimulation to the peri-oral area. Trigeminal neuralgia is very difficult to treat in part due to the lack of an suitable animal model for testing novel therapeutic approaches. This chapter describes a model of trigeminal neuralgia in which crystals of a superabsorbent polymer are placed next to the trigeminal nerve root of rats, producing ongoing mechanical compression of the nerve root. The chapter then describes means of behaviorally assessing the robust mechanical hypersensitivity consequent to the compression that can be used to determine the efficacy of potential therapies for this devastating condition.

Oral Manganese As an MRI Contrast Agent for the Detection of Nociceptive Activity

NMR in Biomedicine. Apr, 2012  |  Pubmed ID: 22447731

The ability of divalent manganese to enter neurons via calcium channels makes manganese an excellent MRI contrast agent for the imaging of nociception, the afferent neuronal encoding of pain perception. There is growing evidence that nociceptive neurons possess increased expression and activity of calcium channels, which would allow for the selective accumulation of manganese at these sites. In this study, we show that oral manganese chloride leads to increased enhancement of peripheral nerves involved in nociception on T(1)-weighted MRI. Oral rather than intravenous administration was chosen for its potentially better safety profile, making it a better candidate for clinical translation with important applications, such as pain diagnosis, therapy and research. The spared nerve injury (SNI) model of neuropathic pain was used for the purposes of this study. SNI rats were given, sequentially, increasing amounts of manganese chloride (lowest, 2.29 mg/100 g weight; highest, 20.6 mg/100 g weight) with alanine and vitamin D(3) by oral gavage. Compared with controls, SNI rats demonstrated increased signal-to-background ratios on T(1)-weighted fast spin echo MRI, which was confirmed by and correlated strongly with spectrometry measurements of nerve manganese concentration. We also found the difference between SNI and control rats to be greater at 48 h than at 24 h after dosing, indicating increased manganese retention in addition to increased manganese uptake in nociceptive nerves. This study demonstrates that oral manganese is a viable method for the imaging of nerves associated with increased nociceptive activity.

Cytokine Expression in the Epidural Space: A Model of Non-compressive Disc Herniation-induced Inflammation

Spine. May, 2012  |  Pubmed ID: 22648034

STRUCTURED ABSTRACT: Study Design. Animal studyObjective. Development of an animal model for the study of biochemical changes that occur in the epidural space after intervertebral disc herniation.Summary of Background Data. Although strong evidence for an inflammatory component exists, the biochemical processes underlying pain following disc herniation remain unknown.Methods. Epidural lavage was performed in 48 rats after L5 dorsal root ganglion (DRG) exposure at baseline and 3, 6, or 24 hours after placement of autologous nucleus pulposus (NP) (N = 15), saline (N = 15), or NP + an interferon-gamma antibody (anti-IFNγ; N = 18) directly onto the DRG. Multiplex assays quantifying interleukin (IL-)-1-α, IL-1β, IL-2, IL-4, IL-6, IL-10, TNFα, IFNγ and GM-CSF were performed. NP (N = 7) was also analyzed for these cytokines by placing NP into saline and measuring the relative concentration.Results. Cytokines measured low at baseline (0-100pg/ml) in all groups. Compared to saline, NP application caused IL-6 elevation, peaking at T = 3hr, that was prevented by anti-IFNγ. NP induced elevation of TNFα, peaking at T = 24hr and was prevented by anti-IFNγ. IFNγ was elevated after NP at T = 3hr and T = 24hr. IL-1α was similar after saline versus NP. The concentrations of IL-1β and IL-10 were elevated at T = 3hr, 6hr and 24hr in all groups without between-groups difference. The level of IL-4 peaked at T = 3hr in the NP group and was different than saline and NP +anti-IFNγ groups but the time effect was insignificant. There was no change for GM-CSF. The concentration of cytokines measured in normal NP was < 2pg/ml for all cytokines except TNFα.Conclusion. In this model of acute non-compressive disc herniation, NP caused the elevation of epidural IL-6, TNFα and IFNγ; all attenuated by IFNγ blockade. IL-1β and IL-10 were both significantly elevated by saline alone and their response was not prevented by IFNγ blockade. This model may prove useful for the study of the biochemical processes by which NP induces inflammation-induced nerve root irritation and radiculopathic pain.

Preprotachykinin-a Gene Disruption Attenuates Nociceptive Sensitivity After Opioid Administration and Incision by Peripheral and Spinal Mechanisms in Mice

The Journal of Pain : Official Journal of the American Pain Society. Oct, 2012  |  Pubmed ID: 23031399

The preprotachykinin A gene (ppt-A) codes for Substance P (SP), supports nociceptive sensitization, and modulates inflammatory responses after incision. Repeated opioid use produces paradoxical pain sensitization-termed opioid-induced hyperalgesia (OIH) -which can exacerbate pain after incision. Here the contribution of SP to peri-incisional nociceptive sensitization and nociceptive mediator production after opioid treatment was examined utilizing ppt-A knockout (-/-) mice and the neurokinin (NK1) receptor antagonist LY303870. Less mechanical allodynia was observed in ppt-A(-/-) mice compared to wild types (wt) after morphine treatment both before and after incision. Moreover, LY303870 administered with morphine reduced incisional hyperalgesia in wt mice. Incision after saline or escalating morphine treatment upregulated skin IL-1β, IL-6, G-CSF and MIP-1α levels in ppt-A(-/-) and wt mice similarly. However, chronic morphine treatment greatly exacerbated increases in skin nerve growth factor levels after incision, an effect entirely dependent upon intact SP signaling. Additionally, SP dependent upregulation of prodynorphin, NMDA1 and NK1 receptor expression in spinal cord was seen after morphine treatment and incision. A similar pattern was seen for 5-HT3 receptor expression in tissue from dorsal root ganglia. Therefore, SP may work at both central and peripheral sites to enhance nociceptive sensitization after morphine treatment and incision. PERSPECTIVE: These studies show that SP signaling modulates enhanced nerve growth factor production and changes in neuronal gene expression seen after incision in mice previously exposed to morphine.