Neuropharmacology
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Vanilloid receptor 1 (TRPV1) antagonists are known to attenuate the neuropathic pain symptoms in peripheral nerve injury models, but the mechanism(s) of their effect remains unclear. At the same time, the role of spinal TRPV1 in pain transduction system has not been fully understood. In this study, the role of spinal TRPV1 in mechanical allodynia in rat chronic constriction injury (CCI) model was investigated. ⋯ TRPV1 protein levels were significantly increased in the ipsilateral side of the lumbar spinal cord at 7 and 14 days following CCI surgery, but not in the contralateral side. Furthermore, capsaicin (300 nM)-evoked release of CGRP-LI was significantly higher in the ipsilateral spinal cord of CCI rats (14 days after surgery) than that of sham-operated rats. These findings suggest that an increased sensitization of the spinal TRPV1 through its up-regulation is involved in the development and/or maintenance of mechanical allodynia in rat CCI model.
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The paraventricular nucleus of the hypothalamus (PVN) is the target of converging orexigenic and anorexigenic pathways originating from various hypothalamic sites and is, therefore, considered to be the chief site mediating hypothalamic regulation of energy homeostasis. Although a large body of evidence suggests that central CB(1) cannabinoid receptors mediate food intake, it is not clear whether PVN CB(1) receptors are involved in the control of feeding behaviour. The present study therefore examined the effects of intra-PVN administration of Delta(9)-tetrahydrocannabinol (THC) and the cannabinoid receptor antagonist SR 141716 on feeding. ⋯ Intra-PVN administration of THC produced a significant increase in food intake that was attenuated by SR 141716. Administration of SR 141716 alone did not affect feeding. Locomotor activity was not significantly affected by any drug treatments, suggesting that effects on feeding were not due to a non-specific reduction in motivated behaviour. These findings suggest an important role for PVN cannabinoid signalling in mediating THC-induced feeding behaviour. These results also demonstrate that the blockade of PVN CB(1) receptors alone is insufficient to reduce baseline feeding behaviour under these conditions.
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Neuropathic pain affects many patients, and treatment today is far from being perfect. Nav1.8 Na(+) channels, which are expressed by small fibre sensory neurons, are promising targets for novel analgesics. Na(+) channel blockers used today, however, show only limited selectivity for this channel subtype, and can cause dose-limiting side effects. ⋯ Ambroxol (1g/kg) was only weakly effective in models for acute pain, but effectively reduced pain symptoms in all other models; in some cases it completely reversed pain behaviour. In most cases the effects were more pronounced than those of gabapentin (at 100mg/kg). These data show that a Nav1.8-preferring Na(+) channel blocker can effectively suppress pain symptoms in a variety of models for chronic, neuropathic and inflammatory pain at plasma levels, which can be achieved in the clinic.
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Recent research in our laboratory has demonstrated that stress activates an endogenous cannabinoid mechanism that suppresses sensitivity to pain [Nature 435 (2005) 1108]. In this work, CB(1) antagonists administered systemically blocked stress-induced analgesia induced by brief, continuous foot-shock. The present studies were conducted to examine the role of cannabinoid CB(1) receptors in the brainstem rostral ventromedial medulla (RVM) and midbrain dorsolateral periaqueductal gray (PAG) in cannabinoid stress-induced analgesia (SIA). ⋯ Palmitoyltrifluoromethylketone, a potent inhibitor of FAAH and phospholipase A2 activity, administered systemically, exerted similar effects. In all conditions, the antinociceptive effects of each FAAH inhibitor were completely blocked by coadministration of the CB(1) antagonist rimonabant. The present results provide evidence that a descending cannabinergic neural system is activated by environmental stressors to modulate pain sensitivity in a CB(1)-dependent manner.