INHIBITION BY SPINAL MORPHINE OF THE TAIL-FLICK RESPONSE IS ATTENUATED IN RATS WITH NERVE LIGATION INJURY

Nerve ligation injury in rats produces increased sensitivity and exaggerated responses to nociceptive stimuli (hyperalgesia) as well as nociceptive responses to normally innocuous stimuli (allodynia) analogous to clinical conditions of neuropathic pain. However, the effect of nerve injury on acute nociception has not been extensively studied. Nerve ligation injury was produced by unilateral ligation of the L5 and L6 spinal roots of the sciatic nerve of male Sprague-Dawley rats. Intrathecal (i.th.) catheters were inserted for spinal drug administration. Response to acute nociception was measured by determining the latency to a rapid flick of the tail (TF) after immersion into a 55 degrees C water bath before (control) and after i.th. morphine administration. No change in baseline response to the nociceptive stimulus was observed in either sham-operated or nerve-injured rats. In sham-operated rats, morphine produced dose-dependent antinociception with a 97 +/- 2.3% maximal possible effect (MPE) at a 60 mu g dose; in these controls A(50) (95% CL) was 22 mu g (17-30 mu g). Morphine administered to rats with nerve injury also produced dose-dependent increase in TF latency, but an MPE of only 60 +/- 17% was obtained at 100 mu g; higher doses elicited signs of behavioral toxicity. While it was not possible to produce a proper dose-response curve with i.th. morphine in animals with nerve injury, an estimation of the A(50) showed approximately a four-fold loss of potency compared to sham-operated controls. Antinociception was readily reversed by naloxone (5 mg/kg, i.p.) in both groups. These data indicate that nerve ligation injury reduces the potency and efficacy of i.th. morphine. While the reasons for this loss of morphine activity in nerve injured animals are unknown, it is possible to speculate that (a) degeneration of primary afferents subsequent to nerve ligation injury might result in a loss of presynaptic opioid (mu?) receptors in the dorsal horn, thereby reducing the antinociceptive activity of morphine at the spinal level; (b) changes in the efficiency of post-receptor transduction may occur following nerve injury which can reduce opioid efficacy; (c) changes in levels of spinal neurotransmitters (e.g., cholecystokinin) may act to diminish opioid action; or (d) sustained afferent input from the site of the injury may be important in limiting the activity of opioids.