Selective inhibition from the anterior hypothalamus of C- versus A-fibre mediated spinal nociception.

Modulation of spinal nociception from the anterior hypothalamus/preoptic area (AH/POA), and consequent alterations in the pain experience may contribute to integrated responses brought into play during fear or stress and as part of the sickness response. This study was designed to compare the effects of descending control from AH/POA on A- versus C-fibre-evoked spinal nociception, since any differential control is of behavioural and clinical importance given that A-fibre and C-fibre nociceptors convey different qualities of the pain signal (first and second pain, respectively), and play different roles in the development and maintenance of chronic pain states. In anaesthetised rats, electromyographic responses were recorded to monitor thresholds of withdrawal to slow (2.5 degrees Cs(-1)) or fast (7.5 degrees Cs(-1)) rates of skin heating of the hindpaw, to preferentially activate C- or A-nociceptors, respectively. Neuronal activation by microinjection of dl-homocysteic acid at sites within a specific region of AH/POA, lateral area of the anterior hypothalamus (LAAH), significantly increased response thresholds to slow heating rates (p<0.02, n=11), but not those to fast rates of heating (p=0.48, n=10). Injection of DLH adjacent to LAAH (n=9) had no significant effect on responses to slow (n=8) or fast (n=9) rates of skin heating. The functional significance of differential descending control of spinal processing of C- and A-nociceptive inputs is discussed with respect to roles both of the LAAH in pain processing, and of C- and A-nociceptive inputs in acute and chronic pain.

Mrz 2/579, a fast kinetic NMDA channel blocker, reduces the development of morphine tolerance in awake rats.

The purpose of the present study was to investigate whether uncompetitive NMDA antagonists with fast channel blocking kinetics, which show fewer side effects in man than compounds such as ketamine, affect the development of tolerance to continuous exposure to morphine. Rats were trained on the Randall--Selitto apparatus before being implanted, under halothane anaesthesia, with primed mini-osmotic pumps (240 microl/day). Six rats were implanted with a vehicle filled pump, seven with a morphine filled pump (28.8 mg/kg/day), and eight with a pair of pumps, one containing morphine and the other Mrz 2/579, a new NMDA antagonist (40 mg/kg/day). A fourth group was implanted with a morphine filled pump followed 25 h later by a Mrz 2/579 filled pump. Paw withdrawal tests were undertaken immediately before, and at 2, 4, 6, 8, 10, 12, 24, 48 and 72 h after the first pump was implanted. Before pump implantation, withdrawal thresholds were 120+/-7 g (mean+/-SEM, n=30). Vehicle infusion had no effect on withdrawal thresholds, whereas morphine infusion increased them significantly at 2 and 4 h after pump implantation (+2 h: 208+/-14 g; P<0.001 vs. control). From 6 h the antinociception elicited by morphine declined progressively; at 10 h withdrawal thresholds were significantly lower than the 2 h post-treatment value (P<0.001). In rats treated with morphine plus Mrz 2/579, thresholds remained significantly higher between 10--72 h post-implantation than with morphine alone (P<0.05). In contrast, infusion of the same level of Mrz 2/579 once tolerance had developed did not reverse tolerance. These results indicate that fast NMDA channel blockers such as Mrz 2/579 may prove to be useful in enhancing analgesia to continuous morphine administration.

The dominant class of somatosensory neurone recorded in the spinal dorsal horn of awake sheep has wide dynamic range properties.

In order to investigate the properties of dorsal horn neurones in the absence of the distorting influences of anaesthesia, preparative surgery, prior training or excessive restraint, recordings have been made in sheep chronically prepared for single-cell recording. Within the limitations of sampling error of dorsal horn neurones with cutaneous receptive fields, the cell type most frequently encountered had wide dynamic range (WDR; convergent; multireceptive) properties; these accounted for 59% of the 46 neurones that were examined in detail. High-threshold mechanoreceptive (nocispecific) and low-threshold mechanoreceptive neurones formed 11% and 30% of the sample, respectively. These and other data indicate that under normal physiological conditions in the awake state, many spinal neurones do indeed have WDR properties, implying that these cells have an important function in nociceptive processing.

Preparative surgery enhances the direct spinal actions of three injectable anaesthetics in the anaesthetized rat.

In this study we have investigated the influence of preparative surgery on the potency with which a range of injectable anaesthetics depressed nociceptive withdrawal reflexes in anaesthetized, spinalized rats. Drug effects were compared on 2 different preparations, each requiring differing degrees of preparatory surgery. Recordings were made in each case of unitary motoneurone responses to controlled noxious stimuli. The dose-dependent effects of the general anaesthetics alpha-chloralose (20-80 mg/kg i.v.) and alphaxalone/alphadolone (0.5-2 mg/kg) and of the dissociative anaesthetic ketamine (0.5-16 mg/kg) were studied. When the degree of surgical intervention was increased, the reflex response to a uniform mechanical pinch stimulus was facilitated. This enhanced response was more susceptible to the reflex depressant actions of all the compounds studied.