It is well known that drugs, which affect monoaminergic tone, can modify pain perception, either inducing hyperalgesia or analgesia. Among the agents which reduce pain perception are amphetamines whose analgesic action is more than a pharmacological detail. In fact, some success in the management of pain in terminal illness was obtained with Brompton's mixture, which contains an opioid, amphetamine or cocaine, and/or a phenothiazine.
Cathinone also has analgesic effects (1),In fact, we have observed that in mouse cathinone increases the latency in the hot-plate test and inhibits writhing induced by intraperitoneal administration of acetic acid. These analgesic effects of cathinone were prevented not only by catecholamine depletors, such as aplha-methyl-p-thyrosine (MPT) and diethylditiocarbamate (DDC), but also by naloxone, the specific antagonist of opiates. Cathinone was also active in the tail-flick test in rats. But in this case, the doses of cathinone used in mice (20-40 mg/kg) were lethal in rats if associated with the tail-flick test. This is not surprising if we consider that toxicity of amphetamines depends on environmental factors. Surprising was the finding that prolonging of latency induced by cathinone, showed two maxima: the first after 30 minutes and the second after 24 hours. This second effect lasted several days. Both peaks were prevented by catecholamine depletors and by naloxone.
The fact that cathinone induces a long-lasting analgesic effect and that naloxone prevents it, contrasts with the pharmacokinetics of these compounds. In fact, we were not able to find cathinone in the blood of rats 24 hours after administration, and the half-life of naloxone is about one hour. Therefore we think that their late effects might depend on events happening shortly after (or linked to) their administration.
To explore these events, we have based our experiments (2) on the recent view on the modulation of pain perception. This considers that pain perception is modulated by inhibitory pathways which are both opiate and non-opiate and can be activated by environmental stimuli. Very recently, Watkins and Mayer have tried to classify these pathways into neural opiate and non-opiate and hormonal opiate and non-opiate. (3).
Accordingly, first of all we wondered if cathinone analgesia belonged to neural or hormonal class. A suggestion came from the observation that prolonged foot paw shock induces a biphasic analgesia, the second peak occurring after 24 hours (4). We therefore decided to test whether analgesia induced by cathinone was equivalent to stress-induced analgesia and so mediated by hormones.
We found that cathinone, did indeed enhance the increase of ACTH plasma concentration induced by the tail-flick test at both 30 minutes and 24 hours. This enhancement was inhibited by naloxone. Therefore the ACTH response seems to parallel the analgesic response. However, the further experiments carried out do not support an involvement of the adrenohypophyseal axis in the prolonged analgesic effect of cathinone (Tab . 1 . ) .
The first clue in this direction came from the observation that pre treatment with dexamethasone , which suppresses the adenohypophyseal incretion of ACTH, did not affect the analgesic action of cathinone at either 30 minutes or 24 hours.
Recently, Lewis et al. (5) found that a reserpine schedule which depletes adreno-medulla from catecholamines but not from encephalines, inhibits early, but not late analgesic response to prolonged foot shock. This result was considered evidence that late response is of hormonal opiate type. Therefore, applied this model to cathinone analgesia, our results showed that reserpine indifferently prevented early and late analgesic responses to cathinone.
Finally, adrenalectomy performed 2 weeks before the test, did not affect the analgesic response to cathinone.
Taken together, these results suggest that the adrenohypophyseal axis is not involved in analgesia induced by cathinone, even though this agent does affect ACTH incretion.
Neural mediated analgesia:
Our attention was then directed towards the neural class of analgesia. First of all, we tested the possibility that prolonged analgesia induced by cathinone is a conditioned behaviour, in which immobilization in the cage for the tail-flick test is the conditioned stimulus and cathinone administration the unconditioned stimulus. Our results do not support this hypothesis. In fact, if we administered cathinone without any other manipulation and 24 hours later submitted the rats to the tail-flick test, we found that reaction times were significantly prolonged. Therefore , analgesic response to cathinone does not depend on stressful manipulation and is not a conditioned reflex.
Secondly we took into account the specificity of the long lasting analgesia induced by cathinone, and found that 5 mg/ kg cathinone did not significantly change the reaction threshold to the thermic stimulus of the hot plate test either at 30 minutes of 24 hours. But the same rats showed an increased latency when tested for tail-flick 24 hours after the administration of cathinone.
Both hot-plate and tail-flick tests are thermic stimuli, but they follow different neural pathways. In particular, tail-flick involves a spinal reflex, even though under supraspinal control. Therefore, the sum of these results show that prolonged analgesia induced by cathinone belongs to neural class of analgesia and involves spinal and/or supraspinal pathways. These pathways may be opiate, non-opiate or both.
Non-opiate and opiate mechanisms:
With regard to non-opiate pathways, there is a recognized descending system of serotoninergic and noradrenergic fibres which modulates the sensitivity of the spinal cord to pain inputs from the periphery. To date we have no direct evidence of an involvement of such pathways in the analgesic action of cathinone. However, depletion of norepinephrine induced by DDC inhibited early and late analgesia and the same result was obtained depleting serotonin pools by administering p-chlorophenylalanine (pCPA). We also obtained a long lasting analgesia with d amphetamine.
Pharmacological evidence therefore suggests that non-opiate neural pathways are involved in the analgesia induced by cathinone.
With regard to the opiate neural pathways, we have found that naloxone prevents early and late analgesia induced by cathinone, but this is not enough to evidence an opiate mechanism, because many researchers have described non-specific actions of naloxone. We therefore need further evidence of the involvement of opiate pathways in the analgesic action of cathinone, and hope to reach a conclusion with the cross tolerance study between cathinone and morphine, now in progress.
Concluding, cathinone analgesia is an amphetamine-like action, mediated by the activation of inhibitory non-opiate and, possibly, opiate neural pathways.
Therefore, it is a well defined pharmacological effect, with the peculiarity of lasting several days. At this point in the research, one question is obvious: does khat consumption induce analgesia?
It is quite exciting to think that an answer to this question may contribute to a clinical reappraisal of amphetamine analgesia.
These studies have been carried out at the Institute of Medical Pharmacology of the University of Rome and they were financed by a grant from the Italian Ministry of Foreign Affairs.
1. Nencini, P. and Abdullahi M. Ahmed, Pharmacol.Res.Comm. 14, 769, 1982
2. Nencini, P., Abdullahi M. Ahmed, Anania, M.C. and Moscucci M., Manuscript in preparation.
3. Watkins, S.R. and Mayer, D.J., Science 216, 1185, 1982
4. Gray, J., Hyson, R.S., Maier, S.F., Madden, J.V., Barchas, J.D., Science 215, 1409, 1981
5. Lewis, J.W., Tordorff, M.G., Sherman, J.E., Liebeskind, J.C., Science, 217, 557, 1982