Bilateral and differential changes in spinal mu, delta and kappa opioid binding in rats with a painful, unilateral neuropathy

Abstract

Quantitative receptor autoradiography was used to assess mu, delta and kappa opioid binding sites in the lumbar spinal cord of rats with neuropathic pain due to a unilateral chronic constriction injury (CCI) of the sciatic nerve. Sections from spinal segment L4 were obtained from animals of treatment groups (left side CCI, right side sham-operated) at 2, 5 and 10 days post surgery and from control animals (left side sham-operated, right side untreated) 10 days post surgery. Autoradiograms were made of the equilibrium binding of the highly selective opioid radioligands, 3H-sufentanil (mu ligand), 3H-[ d-Pen 2,5]-enkephalin (DPDPE, delta ligand) and 3H-U69593 (Upjohn compound, kappa ligand). Computerized grain counting was performed on discrete regions of the autoradiograms corresponding to areas within laminae I–II, V and X on both sides of the spinal cord; the sciatic nerve's small diameter axons terminate in these areas. With a single exception, there were no changes in binding for any of the ligands in any of the areas at 10 days post surgery in the control animals. The exception was a small increase in kappa binding in laminae I–II on the sham-operated side. After nerve injury, however, there were marked changes (compared to the sham-operated side of the control animals) in the amount of binding for all ligands, and most of these changes were bilateral. Mu binding was significantly increased 2–5 days post injury, bilateral to the injury in laminae V and X but only ipsilateral in laminae I–II. Mu binding in all laminae gradually declined towards control values. By day 10 significant differences remained only in lamina X. Delta binding displayed little change at 2 days post injury but declined gradually thereafter. By day 10 post injury, delta binding was significantly decreased in all three areas; these decreases were bilateral in all areas and approximately equal in laminae V and X but were significantly greater on the nerve-injured side in laminae I–II. Kappa binding displayed a complex pattern of changes at day 2 post injury: a significant increase in ipsilateral laminae I–II and a significant increase in contralateral lamina X but no change on either side in lamina V. There was a rapid decrease in kappa binding in all three areas on both sides of the spinal cord by day 5 post injury, and these decreases were little changed by day 10. At day 5 post injury, these bilateral decreases were approximately equal in all three areas, but at day 10 the decrease in lamina X was significantly greater on the nerve-injured side. The effects on opioid binding may be due to alterations in synaptic activity evoked by spontaneous discharges in primary afferents from the injured nerve, to activity in intraspinal circuitry, or to a pain- or stress-evoked activation of descending pathways. Our observations suggest that rats, and perhaps people, with painful peripheral neuropathies may have altered responses to opiate analgesics, especially for opiates given intrathecally.