THE CONTRIBUTION OF SUPRASPINAL, PERIPHERAL AND INTRINSIC SPINAL CIRCUITS TO THE PATTERN AND MAGNITUDE OF FOS-LIKE IMMUNOREACTIVITY IN THE LUMBAR SPINAL-CORD OF THE RAT WITHDRAWING FROM MORPHINE

Withdrawal from morphine evokes increases in Fos-like immunoreactivity in the spinal cord, particularly in the superficial dorsal horn, lami nae I/II. To determine the origin of the increased Fos-like immunoreac tivity, we selectively targeted central or peripheral opioid receptors with naloxone-methiodide, an antagonist that does not cross the blood -brain barrier, or induced withdrawal after eliminating possible sourc es of input to the superficial dorsal horn. To induce tolerance, we im planted rats with morphine or placebo pellets (75 mg, six pellets over three days). On day 4, withdrawal was precipitated and after 1 h, the rats were killed, their spinal cords removed and 50 mu m transverse s ections of the spinal cord immunoreacted with a rabbit polyclonal anti serum directed against the Fos protein. In placebo-pelleted rats, none of the different procedures, viz. spinal transection, unilateral dors al rhizotomy (L4-S2), neonatal capsaicin treatment or direct intrathec al opioid antagonist injection, induced expression of the Fos protein. However, both spinally transected and rhizotomized withdrawing animal s showed significant increases in Fos-like immunoreactivity in laminae I/II, compared to intact withdrawing rats. Neonatal treatment with ca psaicin, which eliminates C-fibres, did not alter Fos-like-immunoreact ivity. Selective withdrawal of morphine from peripheral opioid recepto rs by naloxone-methiodide did not induce Fos-like immunoreactivity in the lumbar spinal cord greater than that recorded in non-withdrawing r ats. However, intrathecal injection of naloxone-methiodide increased F os-like immunoreactivity in laminae I/II and the ventral horn to a gre ater extent than did subcutaneous injection of naloxone. We hypothesiz e that the increased Fos expression after systemic withdrawal in spina lly-transected rats results From a loss of descending inhibitory contr ol that is activated during withdrawal. The increase in withdrawal-ind uced Fos-like immunoreactivity after rhizotomy may be secondary to los s of inhibitory controls exerted by large diameter primary afferents o r to deafferentation-induced reorganization in the dorsal horn. Since capsaicin did not alter the magnitude of Fos-like immunoreactivity in withdrawing rats, we conclude that hyperactivity of opioid receptor-la den C-fibres is not a necessary contributor to the withdrawal-induced increase in Fos-like immunoreactivity in laminae I and II. Taken toget her with the results recorded after intrathecal injection of naloxone- methiodide in tolerant rats, we conclude that the pattern of lumbar sp inal cord Fos expression following systemic withdrawal is primarily a consequence of increased activity in opioid receptor-containing circui ts intrinsic to the dorsal horn and that the magnitude of Fos expressi on is normally dampened by supraspinal and primary afferent-derived in hibitory inputs. (C) 1997 IBRO. Published by Elsevier Science Ltd.