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Evidence for a novel functional role of cannabinoid CB(2) receptors in the thalamus of neuropathic rats.

Jhaveri MD, Elmes SJ, Richardson D, Barrett DA, Kendall DA, Mason R, Chapman V - Eur. J. Neurosci. (2008)

Bottom Line: A supraspinal location of CB(2) receptors has recently been described.CB(2) agonists are also antinociceptive, although the functional role of supraspinal CB(2) receptors in the control of nociception is unknown.Inhibitory effects of JWH-133 on spontaneous (P < 0.01) and noxious-evoked (P < 0.001) responses of neurons were blocked by the CB(2) antagonist SR144528.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, UK. maulik.jhaveri@nottingham.ac.uk

ABSTRACT
Cannabinoid CB(1) receptors have analgesic effects in models of neuropathic pain, but can also produce psychoactive side-effects. A supraspinal location of CB(2) receptors has recently been described. CB(2) agonists are also antinociceptive, although the functional role of supraspinal CB(2) receptors in the control of nociception is unknown. Herein, we provide evidence that CB(2) receptors in the thalamus play a functional role in the modulation of responses of neurons in the ventral posterior nucleus (VPL) of the thalamus in neuropathic, but not sham-operated, rats. Spontaneous and mechanically evoked activity of VPL neurons was recorded with a multichannel electrode array in anaesthetized spinal nerve-ligated (SNL) rats and compared to sham-operated rats. Intra-VPL administration of the CB(2) agonist JWH-133 (30 ng in 500 nL) significantly reduced spontaneous (P < 0.05), non-noxious (P < 0.001) and noxious (P < 0.01) mechanically evoked responses of VPL neurons in SNL rats, but not in sham-operated rats. Inhibitory effects of JWH-133 on spontaneous (P < 0.01) and noxious-evoked (P < 0.001) responses of neurons were blocked by the CB(2) antagonist SR144528. Local administration of SR144528 alone did not alter spontaneous or evoked responses of VPL neurons, but increased burst activity of VPL neurons in SNL rats. There were, however, no differences in levels of the endocannabinoids anandamide and 2AG in the thalamus of SNL and sham-operated rats. These data suggest that supraspinal CB(2) receptors in the thalamus may contribute to the modulation of neuropathic pain responses.

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Spontaneous and innocuous (7 g) or noxious (65 g) mechanically evoked VPL neuronal activity in (A and B) sham-operated and (C and D) SNL rats prior to pharmacological intervention, presented as a raster plot and PSTH from the same neuron. An innocuous (7 g) or noxious (65 g) mechanical stimulus was applied to the hindpaw receptive field for 5 s, repeated 20 times at 15-s intervals over a 5-min period, and the activity of VPL neurons on the side contralateral to SNL or sham surgery was recorded. Mechanical stimulus trains were applied every 15 min and alternated between application of an innocuous (7 g) and a noxious (65 g) mechanical stimulus. Raster lines represent responses to 20 individual mechanical stimuli and the PSTH is an average response to those stimuli from a single neuron.
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fig02: Spontaneous and innocuous (7 g) or noxious (65 g) mechanically evoked VPL neuronal activity in (A and B) sham-operated and (C and D) SNL rats prior to pharmacological intervention, presented as a raster plot and PSTH from the same neuron. An innocuous (7 g) or noxious (65 g) mechanical stimulus was applied to the hindpaw receptive field for 5 s, repeated 20 times at 15-s intervals over a 5-min period, and the activity of VPL neurons on the side contralateral to SNL or sham surgery was recorded. Mechanical stimulus trains were applied every 15 min and alternated between application of an innocuous (7 g) and a noxious (65 g) mechanical stimulus. Raster lines represent responses to 20 individual mechanical stimuli and the PSTH is an average response to those stimuli from a single neuron.

Mentions: The spontaneous firing of VPL neurons was of a significantly higher frequency in SNL rats than in sham-operated rats (9.9 ± 0.8 and 3.8 ± 0.5 Hz, respectively; P < 0.001; Figs 2 and 3). In SNL rats, 88% of neurons showed burst activity compared to 62% of neurons in sham-operated rats. Furthermore, there was a significantly greater incidence of burst firing of VPL neurons in SNL rats than in sham-operated rats (33.4 ± 2.5 and 12.8 ± 2.1 bursts/min, respectively; P < 0.001; Fig. 3). Seventy-four per cent (73/99 neurons) of the spontaneously active VPL neurons recorded on the side contralateral to sham surgery responded to mechanical stimulation of the hindpaw. Similarly, 82% (341/414 neurons) of spontaneously active neurons recorded in the contralateral VPL of SNL rats responded to mechanical stimulation of the nerve-injured hindpaw (Figs 2 and 3). All of the recorded VPL neurons responded to mechanical stimulation of the receptive field on the hindpaw and exhibited a differential magnitude of firing to innocuous (7 g) vs. noxious (65 g) mechanical stimulation (Figs 2 and 3). Mechanically evoked responses of VPL neurons were significantly greater than basal spontaneous activity (P < 0.001 for both 7 g and 65 g; Fig. 3). Comparison of evoked responses of VPL neurons revealed that noxious (65 g) evoked responses of VPL neurons were significantly greater in SNL rats than in sham-operated rats (P < 0.05; Fig. 3C). Basal spontaneous activity was subtracted from mechanically evoked neuronal activity in order to obtain an absolute value for mechanically evoked neuronal responses. Thus, the marked increase in spontaneous neuronal activity in SNL rats did not contribute to the increase in frequency of firing to the noxious mechanical stimulation in SNL rats.


Evidence for a novel functional role of cannabinoid CB(2) receptors in the thalamus of neuropathic rats.

Jhaveri MD, Elmes SJ, Richardson D, Barrett DA, Kendall DA, Mason R, Chapman V - Eur. J. Neurosci. (2008)

Spontaneous and innocuous (7 g) or noxious (65 g) mechanically evoked VPL neuronal activity in (A and B) sham-operated and (C and D) SNL rats prior to pharmacological intervention, presented as a raster plot and PSTH from the same neuron. An innocuous (7 g) or noxious (65 g) mechanical stimulus was applied to the hindpaw receptive field for 5 s, repeated 20 times at 15-s intervals over a 5-min period, and the activity of VPL neurons on the side contralateral to SNL or sham surgery was recorded. Mechanical stimulus trains were applied every 15 min and alternated between application of an innocuous (7 g) and a noxious (65 g) mechanical stimulus. Raster lines represent responses to 20 individual mechanical stimuli and the PSTH is an average response to those stimuli from a single neuron.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2327204&req=5

fig02: Spontaneous and innocuous (7 g) or noxious (65 g) mechanically evoked VPL neuronal activity in (A and B) sham-operated and (C and D) SNL rats prior to pharmacological intervention, presented as a raster plot and PSTH from the same neuron. An innocuous (7 g) or noxious (65 g) mechanical stimulus was applied to the hindpaw receptive field for 5 s, repeated 20 times at 15-s intervals over a 5-min period, and the activity of VPL neurons on the side contralateral to SNL or sham surgery was recorded. Mechanical stimulus trains were applied every 15 min and alternated between application of an innocuous (7 g) and a noxious (65 g) mechanical stimulus. Raster lines represent responses to 20 individual mechanical stimuli and the PSTH is an average response to those stimuli from a single neuron.
Mentions: The spontaneous firing of VPL neurons was of a significantly higher frequency in SNL rats than in sham-operated rats (9.9 ± 0.8 and 3.8 ± 0.5 Hz, respectively; P < 0.001; Figs 2 and 3). In SNL rats, 88% of neurons showed burst activity compared to 62% of neurons in sham-operated rats. Furthermore, there was a significantly greater incidence of burst firing of VPL neurons in SNL rats than in sham-operated rats (33.4 ± 2.5 and 12.8 ± 2.1 bursts/min, respectively; P < 0.001; Fig. 3). Seventy-four per cent (73/99 neurons) of the spontaneously active VPL neurons recorded on the side contralateral to sham surgery responded to mechanical stimulation of the hindpaw. Similarly, 82% (341/414 neurons) of spontaneously active neurons recorded in the contralateral VPL of SNL rats responded to mechanical stimulation of the nerve-injured hindpaw (Figs 2 and 3). All of the recorded VPL neurons responded to mechanical stimulation of the receptive field on the hindpaw and exhibited a differential magnitude of firing to innocuous (7 g) vs. noxious (65 g) mechanical stimulation (Figs 2 and 3). Mechanically evoked responses of VPL neurons were significantly greater than basal spontaneous activity (P < 0.001 for both 7 g and 65 g; Fig. 3). Comparison of evoked responses of VPL neurons revealed that noxious (65 g) evoked responses of VPL neurons were significantly greater in SNL rats than in sham-operated rats (P < 0.05; Fig. 3C). Basal spontaneous activity was subtracted from mechanically evoked neuronal activity in order to obtain an absolute value for mechanically evoked neuronal responses. Thus, the marked increase in spontaneous neuronal activity in SNL rats did not contribute to the increase in frequency of firing to the noxious mechanical stimulation in SNL rats.

Bottom Line: A supraspinal location of CB(2) receptors has recently been described.CB(2) agonists are also antinociceptive, although the functional role of supraspinal CB(2) receptors in the control of nociception is unknown.Inhibitory effects of JWH-133 on spontaneous (P < 0.01) and noxious-evoked (P < 0.001) responses of neurons were blocked by the CB(2) antagonist SR144528.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, Medical School, University of Nottingham, Nottingham NG7 2UH, UK. maulik.jhaveri@nottingham.ac.uk

ABSTRACT
Cannabinoid CB(1) receptors have analgesic effects in models of neuropathic pain, but can also produce psychoactive side-effects. A supraspinal location of CB(2) receptors has recently been described. CB(2) agonists are also antinociceptive, although the functional role of supraspinal CB(2) receptors in the control of nociception is unknown. Herein, we provide evidence that CB(2) receptors in the thalamus play a functional role in the modulation of responses of neurons in the ventral posterior nucleus (VPL) of the thalamus in neuropathic, but not sham-operated, rats. Spontaneous and mechanically evoked activity of VPL neurons was recorded with a multichannel electrode array in anaesthetized spinal nerve-ligated (SNL) rats and compared to sham-operated rats. Intra-VPL administration of the CB(2) agonist JWH-133 (30 ng in 500 nL) significantly reduced spontaneous (P < 0.05), non-noxious (P < 0.001) and noxious (P < 0.01) mechanically evoked responses of VPL neurons in SNL rats, but not in sham-operated rats. Inhibitory effects of JWH-133 on spontaneous (P < 0.01) and noxious-evoked (P < 0.001) responses of neurons were blocked by the CB(2) antagonist SR144528. Local administration of SR144528 alone did not alter spontaneous or evoked responses of VPL neurons, but increased burst activity of VPL neurons in SNL rats. There were, however, no differences in levels of the endocannabinoids anandamide and 2AG in the thalamus of SNL and sham-operated rats. These data suggest that supraspinal CB(2) receptors in the thalamus may contribute to the modulation of neuropathic pain responses.

Show MeSH
Related in: MedlinePlus