Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea‐pig

1 Antitussive, antinociceptive and respiratory depressant effects of codeine, morphine and H.Tyr. d >‐Arg.Gly.Phe(4‐NO 2 ) Pro.NH 2 (compound BW443C) were investigated in unanaesthetized guinea‐pigs. Antagonism of the antitussive and antinociceptive effects was investigated by the use of nalorphine and N‐methylnalorphine. Naloxone was used to antagonize respiratory depression. 2 Antitussive ED 50 s (with 95% confidence limits) for inhibition of cough induced by citric acid vapour were for codeine, morphine and BW443C respectively, 9.1(5.8‐15), 1.3(0.7‐2.4) and 1.2(0.6‐2.6) mg kg −1 s.c. and 8.7(4.2‐12), 1.6(1.2‐1.9) and 0.67(0.002‐3.3) mg kg −1 , i.v. The antitussive effects of subcutaneous codeine (25 mg kg −1 ) morphine (8.1 mg kg −1 ) and BW443C (2.5 mg kg −1 ) were significantly antagonized by subcutaneous nalorphine (3.0 mg kg −1 ) and N‐methylnalorphine (3.0 mg kg −1 ). 3 In the multiple toe‐pinch test, the antinociceptive ED 50 s (with 95% confidence limits) of codeine and morphine were 18(16–22) and 2.3(0.4‐4.3) mg kg −1 , s.c., respectively. Compound BW443C was ineffective in doses of 2.5 and 10 mg kg −1 s.c., a result consistent with its lacking penetration into the CNS. Subcutaneous nalorphine (3.0 mg kg −1 ) antagonized the antinociceptive action of codeine (25 mg kg −1 ) and morphine (8.1 mg kg −1 ). In contrast, N‐methylnalorphine (3.0 mg kg −1 ) had no significant effect on the antinociceptive action of codeine and morphine, suggesting lack of penetration of the CNS by N‐methylnalorphine. 4 At doses near to the i.v. ED 50 values for the antitussive activity, morphine (1.5 mg kg −1 , i.v.) and codeine (10 mg kg −1 , i.v.) caused small but significant depressions of ventilation (7.0 ±2.3% and 16.5 ± 8.4% respectively). Higher doses of morphine (10, 30 and 60 mg kg −1 , i.v.) caused further dose‐related depression of ventilation (9.6 ± 5.3%, 22.4 ± 6.2% and 36.2 ± 9.6% respectively) whereas codeine (30 and 60 mg kg −1 i.v.) caused stimulation of ventilation which was marked (191.3 ± 43.9%) at 60 mg kg −1 . 5 Compound BW443C in doses of 1 or 10 mg kg −1 , i.v. (approximately equal to, and 10 times the ED 50 for antitussive activity) did not cause significant depression of ventilation. Only at higher doses of 30 and 60 mg kg −1 , i.v. was there a significant decrease in minute volume (13.1 ±6.8% and 15.9 ± 1.89% respectively). The depression of ventilation caused by either BW443C (60 mg kg −1 , i.v.) or morphine (60 mg kg −1 , i.v.) was prevented by pretreatment with naloxone (3 mg kg −1 , i.v.) administered 15 min before morphine or BW443C. 6 These results in the guinea‐pig support the hypothesis that the antitussive action of the opiates codeine and morphine and the opioid pentapeptide BW443C do not require penetration of these drugs into the CNS.