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. 2009 Aug 7:5:45.
doi: 10.1186/1744-8069-5-45.

Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain

Wahida Rahman  1 , Claudia S Bauer, Kirsty Bannister, Jean-Laurent Vonsy, Annette C Dolphin, Anthony H Dickenson
Affiliations

Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain

Wahida Rahman et al. Mol Pain. .

Abstract

Background: Descending facilitation, from the brainstem, promotes spinal neuronal hyperexcitability and behavioural hypersensitivity in many chronic pain states. We have previously demonstrated enhanced descending facilitation onto dorsal horn neurones in a neuropathic pain model, and shown this to enable the analgesic effectiveness of gabapentin. Here we have tested if this hypothesis applies to other pain states by using a combination of approaches in a rat model of osteoarthritis (OA) to ascertain if 1) a role for descending 5HT mediated facilitation exists, and 2) if pregabalin (a newer analogue of gabapentin) is an effective antinociceptive agent in this model. Further, quantitative-PCR experiments were undertaken to analyse the alpha 2 delta-1 and 5-HT3A subunit mRNA levels in L3-6 DRG in order to assess whether changes in these molecular substrates have a bearing on the pharmacological effects of ondansetron and pregabalin in OA.

Results: Osteoarthritis was induced via intra-articular injection of monosodium iodoacetate (MIA) into the knee joint. Control animals were injected with 0.9% saline. Two weeks later in vivo electrophysiology was performed, comparing the effects of spinal ondansetron (10-100 microg/50 microl) or systemic pregabalin (0.3 - 10 mg/kg) on evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimuli in MIA or control rats. In MIA rats, ondansetron significantly inhibited the evoked responses to both innocuous and noxious natural evoked neuronal responses, whereas only inhibition of noxious evoked responses was seen in controls. Pregabalin significantly inhibited neuronal responses in the MIA rats only; this effect was blocked by a pre-administration of spinal ondansetron. Analysis of alpha 2 delta-1 and 5-HT3A subunit mRNA levels in L3-6 DRG revealed a significant increase in alpha 2 delta-1 levels in ipsilateral L3&4 DRG in MIA rats. 5-HT3A subunit mRNA levels were unchanged.

Conclusion: These data suggest descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in alpha 2 delta-1 mRNA levels, may underlie pregabalin's state dependent effects in this model of chronic pain.

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Figures

Figure 1
Figure 1
Behavioural assessment from 3 days before until 14 days after MIA (n = 17) or saline injection (n = 16). A. mechanical and B. cooling stimuli applied to the ipsilateral hind paw. C. ambulatory evoked pain score. MIA injection into the knee resulted in behavioural hypersensitivity as evidenced by the significantly greater number of paw withdrawal responses to mechanical punctate and acetone application, and the observed pain scored on ambulation compared with the saline control rats. *p < 0.05, ** p < 0.01 compared with shams.
Figure 2
Figure 2
Electrophysiological recordings of deep dorsal horn wide dynamic range neuronal responses in MIA (n = 30) and sham rats (n = 34). A) Mean evoked neuronal response of peripheral mechanical stimulation during the 10 second application period. B) Mean after-discharge response of neurons to mechanical stimulation. C) Mean evoked neuronal response of peripheral thermal stimulation during the 10 second application period D. Mean after-discharge response of neurons to thermal stimulation. MIA injection resulted in an overall increase in neuronal excitability. * p < 0.05 compared with sham control data.
Figure 3
Figure 3
Comparison of the effects of spinal administration of ondansetron on the evoked neuronal responses to dynamic brush and mechanical punctate stimulation in sham (n = 8) and MIA (n = 8) rats. The neuronal responses evoked by dynamic brush, von Frey 2 and 8 g stimulation were significantly reduced by 50 and 100 μg of ondansetron in the MIA group. Ondansetron produced no significant effects on the mechanical evoked neuronal responses in the sham group. *p < 0.05 compared with pre- drug baseline control data.
Figure 4
Figure 4
Effects of spinal administration of ondansetron on the evoked neuronal responses to thermal stimulation of the peripheral receptive field area in sham (n = 8) and MIA (n = 8) rats. Ondansetron at 5 μg produced a greater inhibition of the evoked response to 45°C in the MIA group compared with the control group; the effects of the drug on the other thermal stimuli tested were not different between groups. Data are expressed as the mean percentage of pre-drug control values ± S.E.M. *p < 0.05 **p < 0.01 compared with pre- drug baseline control data. §p < 0.05 compared with sham control group.
Figure 5
Figure 5
A comparison of the effects of systemic adminsitration of pregabalin on the electrical evoked responses of spinal dorsal horn neurones in sham (n = 8) and MIA (n = 9) rats. Pregabalin significantly attenuated the evoked A-delta, C-fibre and post discharge neuronal responses in the MIA group only. Data are expressed as the mean percentage of pre-drug control values ± S.E.M. * p < 0.05 significant difference compared with pre- drug baseline control data.
Figure 6
Figure 6
Effects of systemic injection of pregabalin on the evoked neuronal responses to mechanical stimulation of the peripheral receptive field. Pregabalin produced significant inhibition of dynamic brush and mechanical punctate evoked neuronal responses in the MIA treated group (n = 9) compared with pre-drug baseline responses. The drug produced little or no effect in the sham control group (n = 8). Data are expressed as the mean percentage of pre-drug control values ± S.E.M. * p < 0.05 significant difference compared with pre- drug baseline control data.
Figure 7
Figure 7
Effects of systemic injection of pregabalin on the evoked neuronal responses to thermal stimulation of the peripheral receptive field. Pregabalin significantly inhibited the thermal evoked neuronal responses in the MIA group (n = 9) compared with pre-drug baseline responses. The drug produced little or no effect in the sham control group (n = 8). Data are expressed as the mean percentage of pre-drug control values ± S.E.M. * p < 0.05 significant difference compared with pre- drug baseline control data.
Figure 8
Figure 8
A and B. Comparison of the effects of pregabalin alone or in the presence of ondansetron on the evoked neuronal responses to mechanical punctate (A) and thermal stimulation (B)of the peripheral receptive field in MIA rats (n = 7). Pregablin alone significantly inhibits the natural evoked neuronal responses. This inhibitory effect of the drug is lost when spinal 5-HT3 receptors are blocked. Data are expressed as the mean percentage of pre-drug control values ± S.E.M. * p < 0.05 significant difference compared with pre-drug baseline controls. C. Quantification of α2δ-1 and 5-HT3A subunit mRNA levels in ipsilateral relative to contralateral DRGs following MIA or saline injection. (C). Mean data for Q-PCR of α2δ-1 in pooled ipsilateral L3/L4 DRGs (ipsi 3+4) or pooled ipsilateral L5/L6DRGs (ipsi 5+6) from either sham (n = 10 and n = 9 respectively) or MIA animals (n = 15 or n = 7 respectively) 14 days after injection. (D). Mean data for Q-PCR of 5-HT3A in pooled ipsilateral L3/L4 DRGs (ipsi 3+4) or pooled ipsilateral L5/L6DRGs (ipsi 5+6) from either sham (n = 7 and n = 7 respectively) or MIA animals (n = 11 or n = 7 respectively). Data are normalized to the respective contralateral side and expressed as the mean percentage of control values ± S.E.M. * p < 0.05 significant difference compared with sham controls.
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