Local peripheral opioid effects and expression of opioid genes in the spinal cord and dorsal root ganglia in neuropathic and inflammatory pain.
We investigated the efficacy of local intraplantar (i.pl.) injection of peptide and non-peptide mu-, delta- and kappa-opioid receptor agonists in rat models of inflammatory and neuropathic pain. Locally applied agonists dose-dependently reduced formalin-induced flinching of the inflamed paw and induced antiallodynic and antihyperalgesic effects in sciatic nerve ligation-induced neuropathic pain. These effects were mediated by peripheral opioid receptors localized at the side of tissue/nerve injury, as was demonstrated by selective and non-selective opioid receptors antagonists. The ED(50) dose range of mu- and kappa-agonists required to induce analgesia in neuropathy was much higher than the ED(50) for inflammation; moreover, only delta-agonists were effective in the same dose range in both pain models. Additionally, effective antinociception was achieved at a lower dose of peptide, compared to non-peptide, opioids. Such findings support the use of the peripheral administration of opioid peptides, especially delta-agonists, in treating chronic pain. Furthermore, in order to assess whether adaptations in the expression of opioid genes could underlie the clinical observation of reduced opioid effectiveness in neuropathic pain, we analyzed the abundance of opioid transcripts in the spinal cord and dorsal root ganglia (DRG) during the neuropathy and inflammation. Nerve injury down-regulated mRNA for all types of opioid receptors in the DRG, which is predicted to decrease in the synthesis of opioid receptors to possibly account for the reduced effectiveness of locally administered opioids in neuropathy. The obtained results differentiate inflammatory and neuropathic pain and provide a novel insight into the peripheral effectiveness of opioids in both types of pain.
Obara
Ilona
I
Department of Pain Pharmacology, Institute of Pharmacology PAS, Smetna 12, 31-343 Krakow, Poland Department of Molecular Neuropharmacology, Institute of Pharmacology PAS, Smetna 12, 31-343 Krakow, Poland.
Parkitna
Jan Rodriguez
JR
Korostynski
Michal
M
Makuch
Wioletta
W
Kaminska
Dorota
D
Przewlocka
Barbara
B
Przewlocki
Ryszard
R
D000700:Analgesics / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000209:etiology / Q000473:pathology; D005557:Formaldehyde / Q000009:adverse effects; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009020:Morphine / Q000494:pharmacology* / Q000627:therapeutic use; D009292:Narcotic Antagonists; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012585:Sciatica / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D000700:Analgesics; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D005557:Formaldehyde; D009020:Morphine