In this review we critically appraise the value of some phasic and tonic nociceptive tests as models for differentiating the antinociceptive effects of opioid agonists. Using heat-evoked withdrawal of the hind paw or tail of a rodent, several early studies have assessed the effects of stimulus intensity upon antinociceptive potency of opioid agonists. After intrathecal (i.t.) administration of either morphine or sufentanil, for example, for any incremental change in stimulus intensity, the degree of right shift in the dose-response relationship was greater for morphine than for sufentanil. At first glance, such data appear to provide robust support for the pharmacological model of fractional receptor occupancy (FRO), which, according to the historical tenets of classical receptor theory, describes the relationship between intrinsic efficacy and the total receptor concentration. However, new data which elegantly characterize the relative contribution of small calibre unmyelinated and myelinated nociceptive afferents in mediating thermal-evoked responses challenge the exclusivity of such explanations with origins in classical theory. Within our review we report the results of experiments which provide direct electrophysiological evidence that noxious skin heating at a low rate activates C-polymodal nociceptors, but does not effectively activate A-delta mechanothermal nociceptors. In contrast, a high rate of skin heating activates both nociceptor classes, but produces a more intense activation of A-delta nociceptors that occurs after a shorter onset latency compared with the activation of C-fibre nociceptors. Thus, in direct challenge to the traditional model of FRO, a shift in the dose-response relationship of morphine to the right with a reduction in efficacy, may reflect the limited effectiveness of morphine to attenuate the A-delta-mediated component which assumes increasing dominance at high intensity heating. In our appraisal of other nociceptive models we provide an in-depth characterization of afferent processing in the early neonate rat, in which opioids have been tested in both phasic (tail flick and hot-plate) and tonic (formalin) tests. Afferent processing in this model is typified by several behavioural, anatomical and functional features which, although not pathological, are characteristic of those observed in models of nerve injury using the adult rat. Notably, these features include a lack of segmental inhibition ('disinhibition') and afferent input in large diameter myelinated fibres which make synaptic contacts within superficial laminae of the dorsal horn that in the adult are predominantly nociceptive. Paradoxically, because this paradigm demonstrates increased sensitivity to the antinociceptive effects of opioids it may have special merit as a model of tonic pain. It was recently announced that the i.t. administration of pertussis toxin (PTX) caused hyperalgesia and allodynia that appears similar to the symptoms reported by patients suffering from neuropathic pain. Unlike the effects of other op...
In an in vivo rat model of myocardial infarction, opioid receptor stimulation has been observed to result in a reduction in infarct size similar to that produced by ischaemic preconditioning. The ability of glibenclamide to abolish this effect suggests an involvement of the myocardial ATP-sensitive potassium (K(ATP)) channel. Importantly, it has recently been demonstrated that glibenclamide can completely abolish the protective effects of preconditioning in humans, suggesting that K(ATP) channel opening may be an endogenous protective mechanism in humans. In this article we report recent findings that indicate that opening of the K(ATP) channel is differentially involved in the antinociceptive effect of some opioids, including buprenorphine, morphine and methadone, but not that of others such as fentanyl or levorphanol. We argue that these findings may also be relevant to the effects of opioids in peripheral tissue, such as the myocardium, and that they may have important clinical ramifications. On the basis of our analysis and interpretation of these in vivo data, we speculate that some opioid agonists, notably buprenorphine, may possess previously unrecognised beneficial cardioprotective effects in some groups of patients, including those undergoing coronary artery bypass and those experiencing an acute myocardial infarction.
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