Biomedical subjects

A S C Rice

Publications and source records attributed to A S C Rice.

7 recordsLinked to original sources

PubMed2007

Cannabinoids and pain.

Convincing evidence from preclinical studies demonstrates that cannabinoids can reduce pain responses in a range of inflammatory and neuropathic pain models. The anatomical and functional data reveal cannabinoid receptor-mediated analgesic actions operating at sites concerned with the transmission and processing of nociceptive signals in brain, spinal cord and the periphery. The precise signalling mechanisms by which cannabinoids produce analgesic effects at these sites remain unclear; however, significant clues point to cannabinoid modulation of the functions of neurone and immune cells that mediate nociceptive and inflammatory responses. Intracellular signalling mechanisms engaged by cannabinoid receptors-like the inhibition of calcium transients and adenylate cyclase, and pre-synaptic modulation of transmitter release-have been demonstrated in some of these cell types and are predicted to play a role in the analgesic effects of cannabinoids. In contrast, the clinical effectiveness of cannabinoids as analgesics is less clear. Progress in this area requires the development of cannabinoids with a more favourable therapeutic index than those currently available for human use, and the testing of their efficacy and side-effects in high-quality clinical trials.

Analgesics↗

PubMed2006

Further characterization of a rat model of varicella zoster virus-associated pain: Relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs.

Persistent herpes zoster-associated pain is a significant clinical problem and an area of largely unmet therapeutic need. Progress in elucidating the underlying pathophysiology of zoster-associated pain and related co-morbidity behavior, in addition to appropriately targeted drug development has been hindered by the lack of an appropriate animal model. This study further characterizes a recently developed rat model of zoster-associated hypersensitivity and investigates (a) response to different viral strains; (b) relationship between viral inoculum concentration ('dose') and mechanical hypersensitivity ('response'); (c) attenuation of virus-associated mechanical hypersensitivity by clinically useful analgesic drugs; and (d) measurement of pain co-morbidity (anxiety-like behavior) and pharmacological intervention in the open field paradigm (in parallel with models of traumatic peripheral nerve injury). Varicella zoster virus was propagated on fibroblast cells before s.c. injection into the glabrous footpad of the left hind limb of adult male Wistar rats. Control animals received injection of uninfected fibroblast cells. Hind-limb reflex withdrawal thresholds to mechanical, noxious thermal and cooling stimuli were recorded at specified intervals post-infection. Infection with all viral strains was associated with a dose-dependent mechanical hypersensitivity but not a thermal or cool hypersensitivity. Systemic treatment with i.p. morphine (2.5 mg/kg), amitriptyline (10 mg/kg), gabapentin (30 mg/kg), (S)-(+)-ibuprofen (20 mg/kg) and the cannabinoid WIN55,212-2 (2 mg/kg) but not the antiviral, acyclovir (50 mg/kg), was associated with a reversal of mechanical paw withdrawal thresholds. In the open field paradigm, virus-infected and nerve-injured animals demonstrated an anxiety-like pattern of ambulation (reduced entry into the central area of the open arena) which was positively correlated with mechanical hypersensitivity. This may reflect pain-related co-morbidity. Further, anxiety-like behavior was attenuated by acute i.p. administration of gabapentin (30 mg/kg) in nerve-injured, but not virus-infected animals. This model will prove useful in elucidating the pathophysiology of zoster-associated pain and provide a tool for pre-clinical screening of analgesic drugs.

Amines↗

PubMed2004

(S)-AMPA inhibits electrically evoked calcitonin gene-related peptide (CGRP) release from the rat dorsal horn: reversal by cannabinoid receptor antagonist SR141716A.

Previous studies in the hippocampus and cerebellum demonstrate that depolarisation of postsynaptic neurones stimulates the rapid synthesis and release of an endocannabinoid that retrogradely interacts with pre-synaptic CB(1) to modulate neurotransmitter release. This study evaluated whether depolarisation of second order neurones in the dorsal horn of the spinal cord by the AMPA receptor agonist, (S)-AMPA, would modulate sensory neurotransmission via release of endocannabinoids. Using an isolated rat dorsal horn with dorsal root attached in vitro preparation the release of calcitonin gene-related peptide (CGRP) after electrical stimulation of the dorsal roots was measured. Superfusion of either WIN55,212-2 (1 microM) or (S)-AMPA (1 microM) significantly attenuated CGRP release in a CB(1)-dependent manner (SR141716A, 5 microM). This provides indirect pharmacological evidence for an AMPA-evoked release of endogenous cannabinoids inhibiting peptide release from primary afferent neurons. This study confirms that CGRP release from the dorsal horn is modulated via CB(1) activation. Furthermore a depolarising stimulus also modulates CGRP release, potentially via the release of endogenous cannabinoids.

Animals↗

PubMed2003

Localisation of cannabinoid receptor 1 in rat dorsal root ganglion using in situ hybridisation and immunohistochemistry.

In this study we used in situ hybridisation and double-labelling immunohistochemistry to characterise cannabinoid receptor 1 (CB(1)) expression in rat lumbar dorsal root ganglion (DRG) neurons.Approximately 25% of DRG neurons expressed CB(1) mRNA and displayed immunoreactivity for CB(1). Sixty-nine percent to 82% of CB(1)-expressing cells were also immunoreactive for neurofilament 200, indicative of myelinated A-fibre neurons, which tend to be large- and medium-sized DRG neurons (>600 microm(2)). Approximately 10% of CB1-expressing cells also expressed transient receptor potential vanilloid family ion channel 2 (TRPV2), the noxious heat-transducing channel found in medium to large lightly myelinated Adelta-fibre DRG neurons. Seventeen percent to 26% of CB(1)-expressing cells co-stained using Isolectin B4, 9-10% for calcitonin gene-related peptide and 11-20% for transient receptor potential vanilloid family ion channel 1 (TRPV1), predominantly markers of small non-myelinated C-fibre DRG neurons (<600 microm(2)). These findings suggest that whilst a wide range of DRG neuron phenotypes express CB(1), it is predominantly associated with myelinated fibres.

Animals↗

PubMed2002

[The pharmacology of cannabinoid derivatives: are there applications to treatment of pain?].

OBJECTIVE: To present the cannabinoid system together with recent findings on the pharmacology of these compounds in the treatment of pain. DATA SOURCES: Search through Medline database of articles published in French and English since 1966. Also use of other publications such as books on cannabis. STUDY SELECTION: All the relevant documents within the theme of this review were used. DATA EXTRACTION: All the data linked to the present topic were searched. DATA SYNTHESIS: Recent advances have dramatically increased our understanding of cannabinoid pharmacology. The psychoactive constituents of Cannabis sativa have been isolated, synthetic cannabinoids described and an endocannabinoid system identified, together with its component receptors and ligands. Strong laboratory evidence now underwrites anecdotal claims of cannabinoid analgesia in inflammatory and neuropathic pain. Sites of analgesic action have been identified in brain, spinal cord and the periphery, with the latter two presenting attractive targets for divorcing the analgesic and psychotrophic effects of cannabinoids. Clinical trials are now required, but are hindered by a paucity of cannabinoids of suitable bioavailability and therapeutic ratio. CONCLUSION: The cannabinoid system is a major target in the treatment of pain and its therapeutic potential should be assessed in the near future by the performance of new clinical trials.

Analgesics, Non-Narcotic↗

PubMed2001

Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study.

A multicentre double blind, randomised, placebo controlled 7-week study evaluated the efficacy and safety of gabapentin 1800 or 2400 mg/day in treating postherpetic neuralgia. Three hundred and thirty-four men and women aged at least 18 years (mean 73) received gabapentin 1800 or 2400 mg daily or placebo in three divided doses with a forced titration schedule. The primary outcome measure was change in average daily pain diary score (baseline week v final week). Secondary outcomes included mean weekly sleep interference score; Short Form-McGill Pain Questionnaire (SF-MPQ); Clinician and Patient Global Impression of Change (CGIC/PGIC); Short Form-36 Health Survey (SF-36). From week 1, pain scores showed a significantly greater improvement with gabapentin: the final difference v baseline was -34.5% for the 1800 mg dose, -34.4% for the 2400 mg dose compared with -15.7% for the placebo group. The difference vs. placebo was 18.8% for the 1800 mg dose (95% confidence interval 10.9-26.8%; P<0.01) and 18.7% for the 2400 mg dose (10.7-26.7%; P<0.01). Sleep interference diaries showed a similar pattern. There were significant differences in favour of gabapentin for number of patients reporting >50% reduction in their pain intensity, in the CGIC and PGIC, in the sensory and total scores of the SF-MPQ (both doses), in the visual analogue scale of pain of the SF-MPQ (2400 mg only) and in the vitality, bodily pain and mental health domains of the SF-36. Overall gabapentin was well tolerated. The most common adverse events were dizziness and somnolence, particularly during the titration phase. Thus, this study confirms the role of gabapentin as an efficacious and well-tolerated treatment for postherpetic neuralgia.

Acetates↗

PubMedDate not supplied

Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy.

Analgesia is an important physiological function of the endocannabinoid system and one of significant clinical relevance. This review discusses the analgesic effects of endocannabinoids at spinal and peripheral levels, firstly by describing the physiological framework for analgesia and secondly by reviewing the evidence for analgesic effects of endocannabinoids obtained using animal models of clinical pain conditions. In the spinal cord, CB(1) receptors have been demonstrated in laminae of the dorsal horn intimately concerned with the processing of nociceptive information and the modulation thereof. Similarly, CB(1) receptors have been demonstrated on the cell bodies of primary afferent neurones; however, the exact phenotype of cells which express this receptor requires further elucidation. Local administration, peptide release and electrophysiological studies support the concept of spinally mediated endocannabinoid-induced analgesia. Whilst a proportion of the peripheral analgesic effect of endocannabinoids can be attributed to a neuronal mechanism acting through CB(1) receptors expressed by primary afferent neurones, the antiinflammatory actions of endocannabinoids, mediated through CB(2) receptors, also appears to contribute to local analgesic effects. Possible mechanisms of this CB(2)-mediated effect include the attenuation of NGF-induced mast cell degranulation and of neutrophil accumulation, both of which are processes known to contribute to the generation of inflammatory hyperalgesia. The analgesic effects of cannabinoids have been demonstrated in models of somatic and visceral inflammatory pain and of neuropathic pain, the latter being an important area of therapeutic need. Analgesia is one of the principal therapeutic targets of cannabinoids. This review will discuss the analgesic effects of endocannabinoids in relation to two areas of therapeutic need, persistent inflammation and neuropathic pain. The more general aspects of the role of cannabinoids, endogenous and exogenous, in analgesia have been recently reviewed elsewhere (Rice, Curr Opi Invest Drugs 2001; 2: 399-414; Pertwee, Prog Neurobil 2001; 63: 569-611; Rice, Mackie, In: Evers A. S, ed. Anesthetic Pharmacology: Physiologic Principles and Clinical Practice. St. Louis: Harcourt Health Sciences, 2002). Since a major goal in the development of cannabinoid-based analgesics is to divorce the antinociceptive effects from the psychotrophic effects, the discussion will focus on the antinociceptive effects produced at the spinal cord and/or peripheral level as these areas are the most attractive targets in this regard. A mechanistic discussion of the "framework" for analgesia will be followed by a description of studies examining the role of endocannabinoids in relieving pain; since the elucidation of these effects was undertaken using synthetic cannabinoids, reference will also be made to such studies, in the context of endocannabinoids.

Analgesia↗