mr-1452 and Pain

Rats placed in a cold environment (4 degrees C) for 2 h had a sustained increase in tail flick latency (TFL) as well as an increase in tail pinch latency (TPch) that was often biphasic with an early peak response at 15 min and a later, often higher, peak at 2 h. Plasma beta-endorphin levels after a modest increase at 5 min (24%) declined throughout the remaining time in the cold. The long-acting opioid antagonist naltrexone had no effect on TFL increases but led to greater increases in TPch (P less than 0.04). In morphine-tolerant rats TFL response was the same as in controls but TPch increases were greater (P less than 0.04). Rats exposed to 2 h of cold for 17 or 18 consecutive days generally developed tolerance to the analgesia of cold, i.e. TFL and TPch increases were diminished; however, the response to morphine on day 18 was the same as in rats never exposed to cold. Adrenalectomy and hypophysectomy led to significantly smaller increases in TFL (P less than 0.02 and P less than 0.001, respectively). The TPch response in contrast, was greater in adrenalectomized (P less than 0.001) and the same in hypophysectomized rats compared to sham controls. An opioid kappa receptor antagonist (Mr 1452) given prior to cold reduced both TFL and TPch response during the first hour. Thus the analgesia induced by cold appeared to shift from an early possibly kappa opioid to a later non-opioid form. The TFL effects seemed to be under hormonal influence while the TPch were not.

Topics: Adrenal Glands; Analgesia; Animals; Benzomorphans; Cold Temperature; Endorphins; Male; Morphine; Pain; Pituitary Gland; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa

Topics: Animals; Benzomorphans; Cyclazocine; Dynorphins; Estradiol; Ethylketocyclazocine; Female; Hypothalamo-Hypophyseal System; Male; Ovary; Pain; Pain Measurement; Rats; Rats, Inbred Strains; Structure-Activity Relationship

Opioid antagonists selective for delta-, kappa- and mu-receptor subtypes were administered intrathecally in rats prior to determination of response thresholds to noxious heat, pressure and chemical visceral stimulation. All antagonists induced hyperalgesia differentially with two or more stimuli but delta- and mu-blockade failed to alter writhing activity. Thus, the extent of involvement of an opioid receptor subtype in antinociception depends on the type of noxious stimulation.

Topics: Analgesia; Animals; Benzomorphans; Enkephalin, Leucine; Hyperalgesia; Hyperesthesia; Injections, Spinal; Male; Morphinans; Naloxone; Narcotic Antagonists; Pain; Rats; Receptors, Opioid

Dynorphin A (DYN A) injected intrathecally in the rat produced a significant elevation of the nociceptive threshold, measured by the tail flick test. The highest dose of DYN A (25 nmol) produced maximal elevation of tail flick latency to radiant heat together with hindlimb paralysis and tail flaccidity lasting several hours, thus confirming several previous reports. A lower dose of DYN A (12.5 nmol) produced only a smaller, not constant, short-lasting change in the nociceptive threshold. The vocalization test (electrical stimulation of the tail) gave a different result: the time course curve showed that the antinociceptive effect had worn off 60 min after DYN A 25 nmol. Thus it can be assumed that the prolonged depression of the tail flick reflex was related to motor dysfunction and did not completely reflect the animal's response to painful stimuli. Tolerance to the antinociceptive and motor effects developed after the chronic intrathecal infusion of DYN A with osmotic minipumps. Intrathecal MR 1452 (30 nmol), a purported kappa-receptor blocker, fully prevented the effects of DYN A but not morphine-induced antinociception. Naloxone antagonized DYN A only at a 4 fold higher dose. MR 1452 (90 nmol) administered after DYN A reversed the elevation of the vocalization threshold while tail flick latency remained unmodified. Analysis by high performance liquid chromatography of intrathecally injected radiolabelled DYN A revealed that DYN A was largely broken down about 10 min after its administration. Our results seem to indicate that DYN A in the spinal cord causes alterations in nociception and motor function, clearly distinguishable in time and both mediated by an opioid receptor, probably of the kappa type. However, different mechanism(s), possibly non-opioid in nature, may contribute to the prolonged depression of the tail flick.

Topics: Analgesia; Animals; Benzomorphans; Drug Tolerance; Dynorphins; Male; Naloxone; Pain; Rats; Rats, Inbred Strains; Sensory Thresholds; Spinal Cord

In barbiturate-anaesthetized cats, intravenous naloxone (0.025-0.10 mg/kg) increased the amplitude of monosynaptic reflexes produced by electrical stimulation of the nerves to the biceps-semitendinosus and gastrocnemius muscles and the complex reflexes to electrical stimulation of myelinated afferents of the sural and tibial nerves and reflexes to electrical stimulation of unmyelinated primary afferents of the tibial nerve. Increases in reflexes were also produced by the (-)- but not the (+)-isomer of the opiate antagonist N- furylmethylnormetazocine (both isomers being given in the dose range 0.03-0.20 mg/kg). The doses of naloxone increasing reflexes to C primary afferents had no effect on the responses of some dorsal horn neurones with cutaneous receptive fields to the same stimuli. The results suggest that, in anaesthetized cats, inhibition involving opioid peptides at some stage is present on many motoneurones. This inhibition may have relevance to animal behaviour after injury.

Topics: Animals; Benzomorphans; Cats; Endorphins; Morphinans; Motor Neurons; Naloxone; Neural Inhibition; Pain; Reflex; Reflex, Monosynaptic; Spinal Cord