Spinal antinociceptive actions of μ‐ and κ‐opioids: the importance of stimulus intensity in determining ‘selectivity’ between reflexes to different modalities of noxious stimulus

Abstract

1In electrophysiological experiments in spinalized rats, y-and K-opioids were tested intravenously on the responses of single motoneurones to electronically controlled, alternating noxious heat and noxious pinch stimuli. The effects of u-and K-opioids were compared with those of the general anaesthetic x-chloralose and the dissociative anaesthetic/PCP ligand ketamine. 2 The K-opioids U-50,488 (0.5-16 mg kg'-i.v.) and tifluadom (0.05-1.6 mg kg-1 i.v.) had very similar actions to the p-opioid fentanyl (0.5-16 pg kg '-i.v.). Thus all three agonists reduced thermal and mechanical nociceptive reflexes in parallel and in a dose-dependent manner, but only so long as neuronal responses to the alternating stimuli elicited similar excitability levels in the neurone under study. Ketamine (0.5-16mgkg-1 i.v.) had similar actions to the opioids whereas a-chloralose (20 mg kg -i.v.) had very little effect on neuronal responsiveness. 3 Apparently 'selective' depressions by both p-and K-opioids could be orchestrated by a deliberate mismatch of the intensities of alternating noxious heat and pinch stimuli; as measured by neuronal firing rate, the weaker of the responses to either type of stimulus was invariably reduced to a greater degree. 4 Similar 'selectivity' could be demonstrated for both p-and K-ligands when the weaker and stronger responses were of the same modality, being applied by the same pincher device but with alternating applied force. 5 It is concluded that the 'selective' spinal actions of K-opioids seen in non-thermal over thermal behavioural models of nociception is likely to be related to the relative intensities, rather than the modalities, of the noxious stimuli used. The validity of the interpretation of results obtained in such behavioural studies is discussed.

Spinal effects of four injectable anaesthetics on nociceptive reflexes in rats: a comparison of electrophysiological and behavioural measurements

“…Our examination of the firing rates of motor units prior to drug administration indicates that in the decerebrate preparations, the pinch stimuli elicited a slightly but significantly greater firing rate. This was not, however, associated with any corresponding decrease in the potency of methohexitone or ketamine, as might have been predicted from the previous study (Parsons & Headley, 1989). Equipotency of drug action between the three experimental groups only occurred when the test compound differed from the maintenance anaesthetic.…”

“…Work already carried out in this laboratory (Parsons & Headley, 1989) has shown that if two intensities of pinch are given so that the same motoneurone responds alternately to strong and weak pinch stimuli with high and low firing rates respectively, then the weaker of the responses is invariably reduced to a greater degree by the same dose of drug, whether opiate or anaesthetic. This highlights the importance of matching stimulus intensity if one is to compare the potencies of compounds.…”

“…Since complete dose-response regimes were not performed on all units tested, the traditional mean dose-response analysis was not possible. As higher doses of drug were only tested on those units which were more resistant, the apparent doseresponse curves for the collected data are more shallow than expected (see Parsons & Headley, 1989).…”

Spinal antinociceptive actions and naloxone reversibility of intravenous μ‐ and κ‐opioids in spinalized rats: potency mismatch with values reported for spinal administration

“…Electrophysiological experiments were performed on a-chloralose anaesthetized, spinalized rats according to the protocols and analytical techniques described in the preceding papers (Parsons & Headley, 1989a Figure 4). The agonist was then tested again at regular 30 min intervals until full recovery from the naloxone antagonism was achieved.…”

“…In the preceding paper (Parsons & Headley, 1989a) we have demonstrated that, following intravenous administration in spinalized rats, K-as Yaksh & Noueihed, 1985 and references quoted in Parsons & Headley, 1989a).…”