ABSTRACT
Previous research has demonstrated that the antinociceptive efficacy of opioids decreases with advancing age. This study utilized radioligand binding techniques to determine if this decline is due to a change in the receptor density (Bmax) and/or affinity (measured as Kd) of the mu (mu) and/or delta (delta) opioid receptors in the spinal cord with advancing age. Saturation binding analysis with [3H][d-Ala2,N-methyl-Phe4,Gly5-ol]enkephalin (DAMGO: a mu-opioid selective agonist) and [3H]naltrindole (a delta-opioid selective antagonist) revealed no age-related changes in Bmax for either the mu or delta-opioid receptors. The Kd value for naltrindole was likewise unaffected by age. The Kd value for DAMGO however, was significantly higher in the aged group as compared with the young and mature groups, indicating a decreased affinity of spinal mu-opioid receptors for DAMGO.
Subject(s)
Aging/metabolism , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolism , Spinal Cord/metabolism , Animals , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Enkephalins/metabolism , Male , Naltrexone/analogs & derivatives , Naltrexone/metabolism , Narcotic Antagonists/metabolism , Radioligand Assay , Rats , Rats, Inbred F344 , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid, mu/agonistsABSTRACT
These studies were designed to investigate how the aging process alters the spinal antinociceptive efficacy of mu (mu), delta (delta) and epsilon (epsilon) opioid receptor agonists administered intrathecally (i.t.) in rats. Various doses of the mu agonist DAGO, the delta agonist DPDPE or the putative epsilon beta-endorphin were injected i.t. in young (5-6-month-old), mature (15-16-month-old) and aged (25-26-month-old) Fischer 344 rats. Antinociception was measured using the rat tail-flick analgesiometric assay. The data demonstrated a decline in spinal opioid-induced antinociception as a function of age. For instance, the i.t. dose of DPDPE or beta-endorphin needed to produce antinociception in the 25-26-month-old rats was higher than that needed to elevate tail-flick latency in the young and mature animals. We also noted that the i.t. doses of the opioid agonists needed to produce 'antinociception' in the aged cohort were within a range of spinal doses that produced motor impairment. Apparently, the aging process alters the ability of opioid receptors to mediate antinociception. Perhaps an age-related decrease in the number and/or affinity of opioid receptor sites in the rat spinal cord accounts for these observations.
Subject(s)
Aging/physiology , Analgesics/pharmacology , Enkephalins/pharmacology , Pain/physiopathology , Spine/physiology , beta-Endorphin/pharmacology , Analysis of Variance , Animals , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Enkephalin, D-Penicillamine (2,5)- , Enkephalins/administration & dosage , Injections, Spinal , Male , Rats , Rats, Inbred F344 , Spine/drug effects , Spine/growth & development , beta-Endorphin/administration & dosageABSTRACT
Initial experiments were conducted to determine whether or not the aging process alters the ability of young, mature, or aged male Fischer 344 rats (5- to 6-, 15- to 16-, and 25- to 26-months-old, respectively) to respond to thermal nociceptive stimuli. Using the tail-flick analgesiometric assay, 25- to 26-month-old rats responded significantly faster to the heat source than 15- to 16-month-old animals, but no significant differences were noted between the 5- to 6-month-old and aged rats. Another series of investigations compared the effects of aging on the spinal antinociceptive properties of the mu opioid agonist [D-Ala2,N-methyl-Phe4,Gly5-ol] enkephalin (DAMPGO) and the delta agonist [D-Pen2,D-Pen5] enkephalin (DPDPE). In these studies, young, mature, and aged rats were injected intrathecally (IT) with different doses of DAMPGO or DPDPE, and opioid-induced antinociception was tested on the tail-flick test. All three age groups responded to IT DAMPGO in a dose-dependent manner but, for the most part, higher spinal doses were required to produce significant elevations in tail-flick latency in the aged cohort of rats. The spinal analgesic effects of DPDPE also declined with advanced age. The aging process apparently alters the pain-inhibitory function of mu and delta opioid receptors in the rat spinal cord.
