T.W. Ford

Adrenergic and opioidergic modulation of a spinal reflex in the decerebrated rabbit.

1. In the decerebrated and spinalized rabbit, electrical stimulation of the sural nerve evokes a short‐latency reflex in the ipsilateral ankle extensor gastrocnemius medialis (GM) which is tonically suppressed by endogenous opioids. In the present study we have investigated the inhibitory influences affecting this reflex in non‐spinalized, decerebrated rabbits. 2. In non‐spinalized rabbits, the thresholds and latencies of the sural‐GM reflex were significantly higher than in spinalized preparations. The opioid antagonist naloxone and the alpha‐adrenoceptor antagonist idazoxan potentiated the reflex in both preparations. Naloxone was significantly more effective in spinalized rabbits whereas idazoxan had a much larger effect in non‐spinalized animals. 3. When the spinal cord was sectioned in the presence of naloxone alone, the GM reflex always increased in size. An ipsilateral hemisection of the cord was as effective as total section in this respect. When the section was performed in the presence of idazoxan and naloxone, the response usually decreased in size. 4. The alpha 2‐adrenoceptor agonist clonidine depressed the reflex in spinalized rabbits, an action that was reversed by idazoxan but not by naloxone. 5. These data show that in the decerebrated, non‐spinalized rabbit, the sural‐GM reflex is tonically suppressed by endogenous opioids, presumably acting at the segmental level, and by an ipsilateral descending pathway which involves an alpha‐adrenoceptor‐mediated synapse. Activity in this descending pathway masks the facilitatory effects of opioid antagonists on spinal reflexes in this preparation.

Prolonged inhibition of a spinal reflex after intense stimulation of distant peripheral nerves in the decerebrated rabbit

1. In decerebrated rabbits, repetitive stimulation of the high‐threshold afferents of the left common peroneal (CP) nerve evokes prolonged depression of the sural‐gastrocnemius medialis (GM) reflex recorded in the same limb. This inhibition is antagonized by co‐administration of the opioid antagonist naloxone with the alpha 2‐adrenoceptor antagonist idazoxan. The present study was designed to investigate whether such inhibition could be elicited from the contralateral hindlimb or the forelimbs. 2. The sural‐GM reflex of decerebrated rabbits was depressed for more than 15 min after stimulation of either ipsilateral or contralateral common peroneal (CP) or median nerves with 500 pulses of 20 V, 1 ms given at 5 Hz. The order of efficacy for generating this inhibition was ipsilateral CP greater than contralateral CP greater than or equal to ipsilateral median = contralateral median. In three of thirty‐nine rabbits, stimulation of the median nerves caused facilitation of the sural‐GM reflex. 3. Idazoxan (1‐2 mg/kg I.V.) did not significantly alter the depressant effect of ipsilateral CP stimulation but reduced that evoked by either median nerve and almost abolished the inhibition evoked from the contralateral CP nerve. 4. Naloxone (0.25 mg/kg I.V.) reduced the effects of ipsilateral CP stimulation, did not alter the inhibition evoked from contralateral CP, and had equivocal actions on the responses to median nerve stimulation. 5. When given together, the two antagonists almost abolished the effects of stimulating the median nerves and the contralateral CP nerve, and markedly reduced the inhibition evoked from the ipsilateral CP nerve. 6. These data show that prolonged inhibition of the sural‐GM reflex can be evoked by stimulation of nerves in all four limbs and that in each case the inhibition can be blocked or reduced by co‐administration of antagonists to opioid and alpha 2‐adrenergic receptors. Such persistent inhibition of reflexes may serve to inhibit withdrawal reflexes in situations where interruptions to normal movement would be disadvantageous.

Noxious stimulation of the toes evokes long-lasting, naloxone-reversible suppression of the sural-gastrocnemius reflex in the rabbit

Repetitive stimulation of the small myelinated and non-myelinated afferents of the common peroneal (c.p.) nerve evokes a long-lasting (20-25 min), naloxone-reversible inhibition of the sural-gastrocnemius reflex in the decerebrated and spinalized rabbit. Altering the number and frequency of stimuli applied to the c.p. nerve showed that this inhibition was dependent on temporal summation of afferent input from that nerve, and that the optimum frequency for producing the effect was between 2 and 10 Hz. Application of natural conditioning stimuli in and around the receptive field of the c.p. nerve showed that noxious, but not innocuous, mechanical and thermal stimuli could evoke long-lasting inhibition of the sural-gastrocnemius reflex. Thermal stimuli produced a biphasic change in the excitability of the reflex with facilitation followed by inhibition. The opioid antagonist naloxone (250 micrograms.kg-1) blocked all suppression resulting from these natural noxious stimuli. Chemical stimulation of the skin with mustard oil did not evoke naloxone-reversible inhibition of the reflex. These results indicate that intensely noxious stimuli can promote the release of opioid peptides in the spinal cord, and that one of the functions of these peptides may be to regulate the level of excitability in withdrawal reflex pathways.

Prolonged potentiation of transmission through a withdrawal reflex pathway after noxious stimulation of the heel in the rabbit

&NA; The sural‐gastrocnemius reflex of the spinalized rabbit was potentiated to an average of 3–6 times control levels after the application of noxious mechanical, thermal or chemical stimuli to the skin of the heel. Facilitation of the reflex was maximal within 1 min of the noxious stimulus, and in many cases persisted for more than 1 h. Prolonged increases in the excitability of the sural‐gastrocnemius reflex were not seen after innocuous mechanical or thermal stimulation of the heel. Repetitive electrical stimulation of the sural nerve (100 shocks given at 0.5 Hz) caused persistent facilitation of the reflex when small myelinated A&dgr; fibres or non‐myelinated C‐fibres were recruited by the conditioning stimulus. Such protracted increases in the excitability of the sural‐gastrocnemius pathway would enhance the protective functions of this reflex. The mechanisms described here have probably evolved to provide a high level of reflex protection to the heel after tissue damage has occurred at that site.

Opioidergic inhibition of flexor and extensor reflexes in the rabbit.

1. Recordings were made from gastrocnemius medialis (GM), semitendinosus (ST) and tibialis anterior/extensor digitorum longus (TA/EDL) motor nerves during mechanical and electrical stimulation of the skin of the foot in decerebrated and spinalized rabbits. 2. GM motoneurones were excited from the heel and not from the toes, whereas TA/EDL responded to stimulation at the toes but not at the heel. ST also responded to electrical and mechanical stimulation at the toes, but there was a disparity between the effects of the two types of stimuli when they were applied at the heel: ST motoneurones fired in response to electrical stimulation of the heel but showed only an ‘off’ response to mechanical stimulation at this site. 3. The opioid antagonist naloxone caused a dose‐dependent increase in all reflexes evoked by electrical stimulation of the skin. The heel‐GM, toes‐ST and toes‐TA/EDL reflexes all increased to more than 3 times control levels with naloxone, which also caused significant decreases in the latencies of these reflex responses. On the other hand, the heel‐ST response increased to just 1.4 times control levels and showed no decrease in latency with the opioid antagonist. 4. These data suggest that segmental withdrawal reflex pathways in the rabbit are suppressed by endogenous opioid peptides. This opioid‐mediated inhibition seems to operate non‐selectively on reflex pathways between cutaneous afferents and motoneurones.

Activation by high intensity peripheral nerve stimulation of adrenergic and opioidergic inhibition of a spinal reflex in the decerebrated rabbit

The short-latency sural to gastrocnemius reflex in the decerebrated rabbit was depressed for 20-30 min following high intensity conditioning stimulation of the common peroneal nerve. This effect was observed in animals with or without spinal section, but was greater in non-spinalized preparations. Graded conditioning stimuli showed that it was necessary to activate fine myelinated common peroneal axons to inhibit the reflex. In spinalized rabbits, maximal inhibition was achieved with conditioning stimulation of fine myelinated axons and was completely reversed by the opioid antagonist naloxone. In non-spinalized rabbits, maximal inhibition was only obtained with conditioning stimuli which activated non-myelinated axons. In these preparations the effects of common peroneal nerve stimuli were only blocked by co-administration of naloxone with the alpha 2-adrenoceptor antagonist idazoxan. Thus high intensity peripheral nerve stimuli activated a segmental opioidergic and a supraspinal adrenergic suppression of the sural-gastrocnemius withdrawal reflex. Such long-lasting suppression of reflex excitability may contribute to recovery from intensely noxious stimuli.

Thyrotropin releasing hormone, cholecystokinin and endogenous opioids in the modulation of spinal reflexes in the rabbit

Electrical stimulation of the sural nerve of the rabbit evokes reflexes in the ipsilateral ankle extensor gastrocnemius medialis and in the knee flexor semitendinosus which are differentially modulated by endogenous opioids. Intravenous injection of the putative functional opioid antagonist, thyrotropin releasing hormone (TRH) or its analogue RX77368, caused the extensor response to double in size and the flexor reflex to increase to 1.5-1.7 times pre-drug controls. The opioid RX77368 had no effect on the naloxone-reversible inhibition of the gastrocnemius reflex which followed tetanic stimulation of the fine afferent fibres of the common peroneal or sural nerves. The cholecystokinin antagonist proglumide, which has been shown to enhance the actions of endogenous opioids in some species, had no effects on either reflex. It is possible that TRH acts as an excitatory neurotransmitter or modulator in the spinal cord of the rabbit opposing, but not blocking, the actions of endogenous opioids.

Opioidergic inhibition of reflexes evoked by selective stimulation of sural nerve C fibres in the rabbit

Reflexes were evoked in the gastrocnemius medialis (GM) muscle nerve by selective electrical stimulation of the non‐myelinated C fibres of the ipsilateral sural nerve of decerebrated, spinalized rabbits. The opioid antagonist (‐)‐quadazocine (555 micrograms/kg i.v.) enhanced responses to sural C fibre stimulation to an average of 236% of pre‐drug levels. In addition, C fibre‐evoked reflexes were depressed for 7‐9 min after repetitive activation of the high threshold axons of the common peroneal nerve, and this effect was reversed after quadazocine. Thus, GM responses to stimulation of non‐myelinated sural afferent fibres are suppressed by endogenous opioid peptides, but the degree of inhibition does not appear to be as profound as that previously reported for reflexes evoked by myelinated fibres.

Noxious stimulation of the heel and of the toes evokes long-lasting increases and decreases in the excitability of the sural-gastrocnemius reflex in the spinalized rabbit

NOXIOUS STIMUI.KTION OF THE HEEL AND OF THE TOES EVOKES LONG-LASTING INCREASES AND DECREASES IN THE EXCITABILITY OF Poster 145 RED Mon-Tues THE SURAL-GASTRO CNEMIUS REFLEX IN THE SPINALIZED RABBIT. R.W.Clarke, T.W.Ford’, J-Harris’, J.S. Pettit’ & J.S.Taylor*, Dept. Physiology & Environmental Science, University of Nottingham, School of Agriculture, Sutton Bonington, Loughborough, Leics LE12 5RD, U.K. Exhibit Hall Abs No 188