Biomedical subjects

I J Lever

Publications and source records attributed to I J Lever.

4 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↗

PubMed2002

CB(1) receptor antagonist SR141716A increases capsaicin-evoked release of Substance P from the adult mouse spinal cord.

Cannabinoids have an antinociceptive action in many pain models. We have investigated a possible modulatory role for Type 1 Cannabinoid receptors (CB(1)) on the release of excitatory transmitter Substance P from the adult mouse spinal cord after stimulation of nociceptor terminals by capsaicin. Capsaicin (0.1 - 10 microM) was applied to superfused cord sections and evoked a dose dependent release of SP above basal outflow of (23.36+/-2.96 fmol 8 ml(-1)). Maximum evoked SP release was obtained with 5 microM Capsaicin (262.4+/-20.8 fmol 8 ml(-1)). Higher capsaicin concentrations (50 - 100 microM) evoked less SP release. Superfusion of CB(1) antagonist SR141716A (5 microM) increased evoked SP release with capsaicin (0.1 - 10 microM) and reversed the reducing effect of high dose capsaicin (100 microM). Antagonism of CB(1) receptors in the spinal cord during capsaicin stimulation, is evidence of tonic CB(1) activity inhibiting the release of excitatory transmitters after activation of nociceptive neurones and is also indicative of endocannabinoid production during noxious stimulation.

Adjuvants, Immunologic↗

PubMed2001

Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation.

Brain-derived neurotrophic factor (BDNF) is synthesized by small neuron cell bodies in the dorsal root ganglia (DRG) and is anterogradely transported to primary afferent terminals in the dorsal horn where it is involved in the modulation of painful stimuli. Here we show that BDNF is released in the rat isolated dorsal horn after chemical stimulation by capsaicin or electrical stimulation of dorsal roots. Capsaicin superfusion (1-100 microm) induced a dose-dependent release of BDNF, measured using ELISA. The highest dose of capsaicin also induced a depletion of BDNF protein in the dorsal horn. BDNF release was also seen after electrical stimulation of the dorsal roots at C-fiber strength. This release was encoded by specific patterns of afferent fiber stimulation. Neither continuous low-frequency (480 pulses, 1 Hz) nor tetanic high-frequency (300 pulses in 3 trains, 100 Hz) stimulation evoked release of BDNF, although substance P (SP) release was observed under both of these conditions. However, BDNF was released after short bursts of high-frequency stimulation (300 pulses in 75 trains, 100 Hz) along with SP and glutamate. The NMDA antagonist d-AP-5 inhibited electrically evoked BDNF release. BDNF release was also measured after systemic or intrathecal NGF treatment. This upregulated BDNF content in the DRG and increased the capsaicin-evoked release of BDNF. Similarly, the amount of BDNF released by burst stimulation was increased after NGF treatment. This activity-dependent release continued to be encoded solely by this stimulation pattern. These experiments demonstrate that BDNF release in the dorsal horn is encoded by specific patterns of afferent fiber stimulation and is mediated by NMDA receptor activation.

Animals↗

PubMed2001

Intrathecally delivered glial cell line-derived neurotrophic factor produces electrically evoked release of somatostatin in the dorsal horn of the spinal cord.

Glial cell line-derived neurotrophic factor (GDNF) is a trophic factor with an established role in sensory neuron development. More recently it has also been shown to support adult sensory neuron survival and exert a neuroprotective effect on damaged sensory neurons. Some adult small-sized dorsal root ganglion (DRG) cells that are GDNF-sensitive sensory neurons express the inhibitory peptide somatostatin (SOM). Thus, we tested the hypothesis that prolonged GDNF administration would regulate SOM expression in sensory neuron cell bodies in the dorsal root ganglia (DRG) and activity-induced release of SOM from axon terminals in the dorsal horn. Continuous intrathecal delivery of GDNF for 11-13 days significantly increased the number of small DRG cells that expressed SOM. Furthermore, GDNF treatment evoked SOM release in the isolated dorsal horn following electrical stimulation of the dorsal roots that was otherwise undetectable in control rats. Conversely capsaicin-induced release of SOM (EC(50) 50 nM) was not modified by GDNF treatment. These results show that GDNF can regulate central synaptic function in SOM-containing sensory neurons.

Animals↗