Pharmacological validation of early and late phase of rat mono-iodoacetate model using the Tekscan system.

BACKGROUND: Previous pharmacological validations of the rat mono-iodoacetate (MIA)-induced chronic joint pain model were mostly performed by measuring weight-bearing (WB) deficit with an incapacitance tester. However, conventional incapacitance testers have several drawbacks including restrain stress on animal and sole use of hind limbs WB. OBJECTIVES: The aim of the present study was to compare pharmacological sensitivity of the early (up to 1 week after MIA) versus late (between 2 and 4 weeks after MIA) phase of the rat MIA model using a highly sensitive tactile pressure measurement system (Tekscan(®)), which can measure weight borne by all four limbs and the tail in a non-restrained animal. METHODS: The Tekscan(®) WB measurement system was used in MIA rats to examine the acute and chronic dosing effects of drugs that targeted different mechanisms. Electrophysiological recordings from joint afferents and biochemical analysis of synovial fluid were also performed. RESULTS: Dexamethasone, duloxetine and morphine significantly alleviated WB deficits in the Tekscan(®) system during both early and late phase of the MIA model while celecoxib and naproxen alleviated WB deficit only during the early phase. Similarly, naproxen was able to inhibit spontaneous neuronal activity from MIA joint afferents only during the early phase. Finally, concentrations of prostaglandin E(2) in synovial fluid were elevated only during the early phase of the rat MIA model. CONCLUSIONS: Our pharmacological validation studies using the Tekscan(®) system along with electrophysiological and biochemical results suggest different mechanisms for early and late phase of MIA-induced chronic joint pain in rat.

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

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.

Intraplantar injection of anandamide inhibits mechanically-evoked responses of spinal neurones via activation of CB2 receptors in anaesthetised rats.

Anti-nociceptive effects of the endocannabinoid anandamide are well established. Anandamide has, however, also been shown to activate pro-nociceptive vanilloid 1 (VR1) receptors present on primary afferent nociceptors. The aim of the present study was to determine the effect of intraplantar injection of anandamide on dorsal spinal neuronal responses in control rats and rats with hindpaw carrageenan-induced inflammation. Effects of intraplantar administration of anandamide (50 microg in 50 microl) on peripheral mechanically-evoked responses of spinal neurones were studied in halothane-anaesthetised rats in vivo. Responses of spinal neurones to mechanical punctate stimulation (von Frey filaments, 8-80 g) of the peripheral receptive field were similar in non-inflamed rats and rats with hindpaw carrageenan-induced inflammation. Intraplantar injection of anandamide, but not vehicle, significantly (P<0.05) inhibited innocuous and noxious mechanically-evoked responses of spinal neurones in rats with hindpaw inflammation, but not in non-inflamed rats. Co-administration of the cannabinoid (2) (CB(2)) receptor antagonist, SR144528 (10 microg in 50 microl), but not the cannabinoid (1) (CB(1)) receptor antagonist, SR141716A (10 microg in 50 microl), significantly blocked inhibitory effects of anandamide on peripheral evoked neuronal responses in rats with hindpaw inflammation. This study demonstrates inhibitory effects of exogenous anandamide on mechanically-evoked responses under inflammatory conditions in vivo, which are mediated by peripheral CB(2) receptors.