The Utility of Peripherally Restricted Kappa-Opioid Receptor Agonists for Inhibiting Below-Level Pain After Spinal Cord Injury in Mice.

Pain after spinal cord injury (SCI) can be difficult to treat. Drugs that target the opioid receptor (OR) outside the central nervous system (CNS) have gained increasing interest in pain control owing to their low risk of central side effects. Asimadoline and ICI-204448 are believed to be peripherally restricted KOR agonists withlimited access to the CNS. This study examined whether they can attenuate pain hypersensitivity in mice subjected to a contusive T10 SCI. Subcutaneous (s.c.) injection of asimadoline (5, 20 mg/kg) and ICI-204448 (1, 10 mg/kg) inhibited heat hypersensitivity at both doses, but only attenuated mechanical hypersensitivity at the high dose. However, the high-dose asimadoline adversely affected animals' exploratory performance in SCI mice and caused aversion, suggesting CNS drug penetration. In contrast, high-dose ICI-204448 did not impair exploration and remained effective in reducing both mechanical and heat hypersensitivities after SCI. Accordingly, we chose to examine the potential peripheral neuronal mechanism for ICI-204448-induced pain inhibition by conducting in vivo calcium imaging of dorsal root ganglion (DRG) in Pirt-GCaMP6s+/- mice. High-dose ICI-204448 (10 mg/kg, s.c.) attenuated the increased fluorescence intensity of lumbar DRG neurons activated by a noxious pinch (400 g) stimulation in SCI mice. In conclusion, systemic administration of ICI-204448 achieved SCI pain inhibition at doses that did not induce notable side effects and attenuated DRG neuronal excitability which may partly contribute to its pain inhibition. These findings suggest that peripherally restricted KOR agonists may be useful for treating SCI pain, but the therapeutic window must be carefully examined.

Role of primary sensory neurone cannabinoid type-1 receptors in pain and the analgesic effects of the peripherally acting agonist CB-13 in mice.

BACKGROUND: Cannabinoid type-1 receptors (CB1Rs) are expressed in primary sensory neurones, but their role in pain modulation remains unclear. METHODS: We produced Pirt-CB1R conditional knockout (cKO) mice to delete CB1Rs in primary sensory neurones selectively, and used behavioural, pharmacological, and electrophysiological approaches to examine the influence of peripheral CB1R signalling on nociceptive and inflammatory pain. RESULTS: Conditional knockout of Pirt-CB1R did not alter mechanical or heat nociceptive thresholds, complete Freund adjuvant-induced inflammation, or heat hyperalgesia in vivo. The intrinsic membrane properties of small-diameter dorsal root ganglion neurones were also comparable between cKO and wild-type mice. Systemic administration of CB-13, a peripherally restricted CB1/CB2R dual agonist (5 mg kg-1), inhibited nociceptive pain and complete Freund adjuvant-induced inflammatory pain. These effects of CB-13 were diminished in Pirt-CB1R cKO mice. In small-diameter neurones from wild-type mice, CB-13 concentration-dependently inhibited high-voltage activated calcium current (HVA-ICa) and induced a rightward shift of the channel open probability curve. The effects of CB-13 were significantly attenuated by AM6545 (a CB1R antagonist) and Pirt-CB1R cKO. CONCLUSION: CB1R signalling in primary sensory neurones did not inhibit nociceptive or inflammatory pain, or the intrinsic excitability of nociceptive neurones. However, peripheral CB1Rs are important for the analgesic effects of systemically administered CB-13. In addition, HVA-ICa inhibition appears to be a key ionic mechanism for CB-13-induced pain inhibition. Thus, peripherally restricted CB1R agonists could have utility for pain treatment.

Neuropathic pain.

Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aß, Aδ and C fibres) and central neurons, and affects 7-10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain.

Effects of Combined Electrical Stimulation of the Dorsal Column and Dorsal Roots on Wide-Dynamic-Range Neuronal Activity in Nerve-Injured Rats.

OBJECTIVES: Electrical stimulation at the dorsal column (DC) and dorsal root (DR) may inhibit spinal wide-dynamic-range (WDR) neuronal activity in nerve-injured rats. The objective of this study was to determine if applying electrical conditioning stimulation (CS) at both sites provides additive or synergistic benefits. MATERIALS AND METHODS: By conducting in vivo extracellular recordings of WDR neurons in rats that had undergone L5 spinal nerve ligation, we tested whether combining 50 Hz CS at the two sites in either a concurrent (2.5 min) or alternate (5 min) pattern inhibits WDR neuronal activity better than CS at DC alone (5 min). The intensities of CS were determined by recording antidromic compound action potentials to graded stimulation at the DC and DR. We measured the current thresholds that resulted in the first detectable Aα/ß waveform (Ab0) and the peak Aα/ß waveform (Ab1) to select CS intensity at each site. The same number of electrical pulses and amount of current were delivered in different patterns to allow comparison. RESULTS: At a moderate intensity of 50% (Ab0 + Ab1), different patterns of CS all attenuated the C-component of WDR neurons in response to graded intracutaneous electrical stimuli (0.1-10 mA, 2 msec) and inhibited windup in response to repetitive noxious stimuli (0.5 Hz). However, the inhibitory effects did not differ significantly between different patterns. At the lower intensity (Ab0), no CS inhibited WDR neurons. CONCLUSIONS: These findings suggest that combined stimulation of DC and DR may not be superior to DC stimulation alone for inhibition of WDR neurons.

Spinal cord stimulation-induced analgesia: electrical stimulation of dorsal column and dorsal roots attenuates dorsal horn neuronal excitability in neuropathic rats.

BACKGROUND: The sites of action and cellular mechanisms by which spinal cord stimulation reduces neuropathic pain remain unclear. METHODS: We examined the effect of bipolar electrical-conditioning stimulation (50 Hz, 0.2 ms, 5 min) of the dorsal column and lumbar dorsal roots on the response properties of spinal wide dynamic range (WDR) neurons in rats after L5 spinal nerve injury. The conditioning stimulation intensity was set at the lowest current that evoked a peak antidromic sciatic Aα/ß-compound action potential without inducing an Aδ- or C-compound action potential. RESULTS: Within 15 min of the dorsal column or root conditioning stimulation, the spontaneous activity rate of WDR neurons was significantly reduced in nerve-injured rats. Conditioning stimulation also significantly attenuated WDR neuronal responses to mechanical stimuli in nerve-injured rats and inhibited the C-component of the neuronal response to graded intracutaneous electrical stimuli applied to the receptive field in nerve-injured and sham-operated rats. It is noteworthy that dorsal column stimulation blocked windup of WDR neuronal response to repetitive intracutaneous electrical stimulation (0.5 Hz) in nerve-injured and sham-operated rats, whereas dorsal root stimulation inhibited windup only in sham-operated rats. Therefore, stimulation of putative spinal substrates at A-fiber intensities with parameters similar to those used by patients with spinal cord stimulators attenuated established WDR neuronal hyperexcitability in the neuropathic condition and counteracted activity-dependent increase in neuronal excitability (i.e., windup). CONCLUSIONS: These results suggest a potential cellular mechanism underlying spinal cord stimulation-induced pain relief. This in vivo model allows the neurophysiologic basis for spinal cord stimulation-induced analgesia to be studied.

Advances in treatment of complex regional pain syndrome: recent insights on a perplexing disease.

PURPOSE OF REVIEW: The paper is a critical appraisal of recent advances in the treatment of complex regional pain syndrome. Rapidly changing concepts related to the pathophysiology of this disease has transformed its current management and necessitates an updated review of the literature. RECENT FINDINGS: Chronic regional pain syndrome is a perplexing disease that continues to challenge researchers with respect to its cause and treatment. Recent modification to diagnostic criteria has enabled clinicians to diagnose this disease in a more consistent fashion. Emerging data indicate a possible role of inflammation in the overall pathophysiology and have led to treatment trials with newer anti-inflammatory medications. Certain 'conventional' interventional techniques have been recently scrutinized. A few novel therapeutic options like graded imagery are also outlined. SUMMARY: Enhanced insight into the pathophysiology of chronic regional pain syndrome has modified current clinical practice and the focus of research. Certain 'standard' therapeutic options for chronic regional pain syndrome have failed the test of time while others have prevailed. New options have recently been evaluated and have shown promising early results. Knowledge of recent advances in chronic regional pain syndrome will help pain physicians provide optimal care to these patients.

Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain.

Nitric oxide (NO) acts as a neurotransmitter or neuromodulator involving in the modulation of thermal and/or inflammatory hyperalgesia. The neuronal nitric oxide synthase (nNOS) is a key enzyme for NO production in normal neuronal tissues, but its functional role in chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical pain hypersensitivity during the maintenance (but not the development) of inflammatory pain, while it failed to attenuate either development or maintenance of CFA-induced thermal pain hypersensitivity. Intraperitoneal administration of L-N(G)-nitro-arginine methyl ester (L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical pain hypersensitivity at both development (2h) and maintenance (24h) phase in wild type mice, but had no effect in the knockout mice. Furthermore, intrathecal injection of either L-NAME or 7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical pain hypersensitivity at both 2 and 24h after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical pain hypersensitivity and that it may also be sufficient for the development of mechanical pain hypersensitivity and for the development and maintenance of thermal pain hypersensitivity after chronic inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory pain.

Tart cherry anthocyanins suppress inflammation-induced pain behavior in rat.

The use of complementary and alternative medicine (CAM) has increased in the United States and more patients are seeking CAM therapies for control of pain. The present investigation tested the efficacy of orally administered anthocyanins extracted from tart cherries on inflammation-induced pain behavior in rats. Paw withdrawal latency to radiant heat and paw withdrawal threshold to von Frey probes were measured. The first set of experiments examined the effects of tart cherry anthocyanins (400 mg/kg) on the nociceptive behaviors and edema associated with inflammation induced by intraplantar injection of 1% carrageenan. These studies also included tests of motor coordination. The second set of experiments determined if tart cherry anthocyanins (15, 85, and 400 mg/kg) dose-dependently affected the inflammation induced by intraplantar injection of 25% complete Freund's adjuvant. We found that tart cherry extracts reduce inflammation-induced thermal hyperalgesia, mechanical hyperalgesia and paw edema. The suppression of thermal hyperalgesia was dose-dependent and the efficacy of highest dose (400 mg/kg) was similar to indomethacin (5 mg/kg). The highest dose anthocyanin (400 mg/kg) had no effects on motor function. These data suggest that tart cherry anthocyanins may have a beneficial role in the treatment of inflammatory pain. The antihyperalgesic effects may be related to the anti-inflammatory and antioxidant properties of anthocyanins. A better understanding of the modulatory role of dietary constituents and phytonutrients on pain will offer further therapeutic options for treating patients with persistent and chronic pain conditions.

Analgesic effects of a soy-containing diet in three murine bone cancer pain models.

UNLABELLED: Bone is a common metastatic site for prostate and breast cancer, and bone cancer is usually associated with severe pain. Traditional treatments for cancer pain can sometimes be ineffective or associated with side effects. Thus an increasing number of patients seek alternative therapies. In this study we investigated the analgesic effects of a soy diet on 3 experimental models of bone cancer pain. Mice were fed a diet in which the protein source was either soy or casein. After 1 week on the diet, sarcoma cells (NCTC 2472) were injected into the medullary cavity of the humeri, femur, or calcaneus. Experimenters blinded to diet of the animal assessed the pain behavior in these animals, forelimb grip force in the humerus model and paw withdrawal frequency to mechanical stimuli in the calcaneus and femur models. The effect of morphine on cancer-induced pain behavior was investigated in calcaneus and femur models. In addition, in the femur model, the effects of soy on tumor size and bone destruction were studied. The soy diet reduced secondary mechanical hyperalgesia in the femur model but had no effect on primary mechanical hyperalgesia in the calcaneus model or on movement-related hyperalgesia in the humerus model. No dietary impact was discerned in measurements of tumor size, bone destruction, and body weight in the femur model, suggesting that the soy diet had no effect on cancer growth. Morphine dose-dependently reduced hyperalgesia with no diet-based difference. These results suggest that a soy diet might provide analgesia in certain forms of hyperalgesia associated with bone cancer. PERSPECTIVE: The study raises the possibility of dietary supplements influencing aspects of cancer pain. Further research will help determine if use of nutritional supplements, such as soy proteins, can reduce opioid analgesic use in chronic pain states and help minimize the side effects associated with long term use of opioids.

Dietary constituents as novel therapies for pain.

The use of complementary and alternative medicine has dramatically increased in the United States. The effects of select dietary constituents in animal models and clinical pain states are reviewed. Specifically, the antinociceptive and analgesic properties of soybeans, sucrose, and tart cherries are discussed. The potential actions of dietary constituents as antiinflammatory and antioxidant agents are presented.

Bioactive terpenoids and guggulusteroids from Commiphora mukul gum resin of potential anti-inflammatory interest.

Guggulu, the gum resin from Commiphora mukul, is one of the components of various formulations of traditional Ayurvedic medicine to treat inflammation, obesity, and lipid disorders. In most preparations of Ayurvedic medicine in India, guggulu is boiled prior to its use. Therefore, guggulu was boiled with H2O prior to extractions in our study. Bioassay-guided isolation of compounds from the hexane-soluble portion of the MeOH extract of guggulu yielded cembrenoids, 1-6, a bicyclic diterpene, 7, guggulusterone derivatives, 8-11, myrrhanone derivatives, 12, myrrhanol derivative, 13, and a lignan, 14. The structures of these compounds were confirmed by spectroscopic methods. Compounds 5, 6, 7, 10, and 12-14 are novel. These compounds were assayed for lipid peroxidation and cyclooxygenase (COX) enzyme inhibitory activities. At 100 ppm, compounds 3, 6, and 14 inhibited the lipid peroxidation by 79, 57, and 58%, respectively, and the rest of isolated compounds showed 20-40% inhibitory activity with respect to the controls. In COX-1 and COX-2 enzyme inhibitory assays, compound 3 showed 79 and 83%, and compound 8 gave 67 and 54% of inhibition, respectively, at 100 ppm. All fourteen compounds inhibited COX-1 enzyme at 100 ppm. The lipid peroxidation and COX enzyme inhibitory activities exhibited by compounds isolated from C. mukul may substantiate its use in traditional medicine.

Spinal cord stimulation for complex regional pain syndrome: an evidence-based medicine review of the literature.

OBJECTIVES: The purpose of this investigation is to assess the evidence for efficacy of SCS in the management of pain in patients with CRPS. SEARCH STRATEGY: Electronic databases such as Medline and Cochrane Library were queried using key words such as "spinal cord stimulation," "reflex sympathetic dystrophy (RSD)," and "complex regional pain syndrome (CRPS)." SELECTION CRITERIA: Relevant published randomized controlled trials (RCT), cohort studies, case-control studies, case series, and case reports that described SCS as the primary treatment modality for patients with CRPS were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Data extracted from qualified studies were summarized in sections of methodology, demographics, SCS equipment, primary and secondary outcomes, and complications. RESULTS: Thirteen studies using the primary search strategy and 7 studies from their reference lists were considered. Five of these 20 studies were discarded. One RCT, 2 prospective observational, and 12 retrospective observational studies were eventually considered. The methodological quality of all studies was poor except for the single RCT study. DISCUSSION: Although limited in quality and quantity, available evidence from the examined literature suggests that SCS is effective in the management of pain in patients with CRPS (grade B/C). Clinically useful information extracted from the available studies is very limited in guiding clinicians in the rational use of SCS for pain management in CRPS patients. Future attempts to investigate the efficacy of SCS in CRPS patients should involve methodologically robust designs such as randomized studies that have sufficient power.

The correlation between dietary soy phytoestrogens and neuropathic pain behavior in rats after partial denervation.

UNLABELLED: Soy diets suppress the development of neuropathic pain behavior in rats undergoing partial sciatic nerve ligation (PSL) injury. Phytoestrogens, plant isoflavones and lignans, abundantly found in soy products, have powerful estrogenic properties. Because, in some preparations, steroid estrogens were found to exert antinociception, we examined whether the analgesic effect of dietary soy is mediated by phytoestrogens. Male Wistar rats were fed five different diets containing 8-180 microg of phytoestrogens per gram. These diets were administered 2 wk before and 2 wk after PSL injury. Levels of tactile allodynia and mechanical and heat hyperalgesia of these rats were determined on Days 3, 8, and 14 after PSL injury. Plasma levels of two major phytoestrogens (genistein and daidzein) and two daidzein metabolites (equol and dihydrodaidzein) were assessed on Day 14 postoperatively. We found that the plasma concentration of these phytoestrogens and the levels of allodynia and hyperalgesia varied highly among dietary groups. Average plasma concentrations of phytoestrogens were associated with reduced levels of tactile allodynia and mechanical hyperalgesia, but not with reduced heat allodynia. Low and high plasma phytoestrogen levels were not analgesic in these tests. This report is the first to show that, at certain plasma concentrations, phytoestrogens reduce neuropathic pain in rats. IMPLICATIONS: Dietary soy suppresses neuropathic pain in rats after partial sciatic nerve ligation. Some of the pain-suppression properties of soy can be attributed to phytoestrogens, isoflavones abundantly found in soy products. Average, but not low or high, plasma levels of phytoestrogens are associated with analgesia.