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


CONCLUSIONS
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.
Rahman
Wahida
W
Department of Neuroscience, Pharmacology and Physiology, University College London, Gower Street, London, WC1E 6BT, UK. w.rahman@ucl.ac.uk
Bauer
Claudia S
CS
Bannister
Kirsty
K
Vonsy
Jean-Laurent
JL
Dolphin
Annette C
AC
Dickenson
Anthony H
AH
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology; D020746:Calcium Channels, L-Type; D004195:Disease Models, Animal; D004594:Electrophysiology; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D000069583:Pregabalin; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000235:genetics / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000700:Analgesics; C486060:Cacna2d1 protein, rat; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D012701:Serotonin; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid